AMPK—activating heterocyclic compounds and methods for using the same

ABSTRACT

Disclosed are substituted pyridine compounds as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure 
                         
wherein E, J, T, the ring system denoted by “B”, T, R 3 , R 4 , w and x are as described herein. In certain embodiments, a compound disclosed herein activates the AMPK pathway, and can be used to treat metabolism-related disorders and conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No. 13/194,810, filed Jul. 29, 2011, which claims the benefit of the earlier filing date of U.S. Provisional Patent Application Ser. No. 61/368,928, filed Jul. 29, 2010. This application is also a divisional of U.S. patent application Ser. No. 13/800,986, filed Mar. 13, 2013, which claims the benefit of the earlier filing date of U.S. Provisional Patent Application Ser. No. 61/368,928, filed Jul. 29, 2010. Each of the above-referenced applications is hereby incorporated herein by reference in its entirety.

BACKGROUND

1. Field

This disclosure relates generally to compounds, pharmaceutical compositions and methods of use of the compounds and compositions containing them. This disclosure relates more particularly to certain substituted pyridine compounds and pharmaceutical compositions thereof, and to methods of treating and preventing metabolic disorders such as type II diabetes, atherosclerosis and cardiovascular disease using certain substituted pyridine compounds.

2. Technical Background

The kinase 5′-AMP-activated protein kinase (AMPK) is well established as an important sensor and regulator of cellular energy homeostasis. Being a multi-substrate enzyme, AMPK regulates a variety of metabolic processes, such as glucose transport, glycolysis and lipid metabolism. It acts as a sensor of cellular energy homeostasis and is activated in response to certain hormones and muscle contraction as well as to intracellular metabolic stress signals such as exercise, ischemia, hypoxia and nutrient deprivation. Once activated, AMPK switches on catabolic pathways (such as fatty acid oxidation and glycolysis) and switches off ATP-consuming pathways (such as lipogenesis). Activation of the AMPK pathway improves insulin sensitivity by directly stimulating glucose uptake in adipocytes and muscle and by increasing fatty acid oxidation in liver and muscle, resulting in reduced circulating fatty acid levels and reduced intracellular triglyceride contents. Moreover, activation of the AMPK pathway decreases glycogen concentration by reducing the activity of glycogen synthase. Activation of the AMPK pathway also plays a protective role against inflammation and atherosclerosis. It suppresses the expression of adhesion molecules in vascular endothelial cells and cytokine production from macrophages, thus inhibiting the inflammatory processes that occur during the early phases of atherosclerosis.

What is needed are compounds, pharmaceutical compositions and methods of using them to treat disease states wherein AMPK activation is beneficial, such as type II diabetes, atherosclerosis and cardiovascular disease.

SUMMARY

Disclosed herein are compounds having structural formula (I)

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), in which

-   -   0 or 1 of D¹, D² and D³ is N, with the others independently         being CH or C substituted by one of the w R³;     -   E is —R², —C(O)NR¹R², —NR¹R² or —NR¹C(O)R², in which R¹ and R²         together with the nitrogen to which they are bound form Hca, or         R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄         alkyl), and R² is —C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₀-C₃         alkyl)-Het, —(C₀-C₃ alkyl)-Cak or —(C₀-C₃ alkyl)-Hca;     -   each R³ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆         haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆         alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆         alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,         —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN;     -   w is 0, 1, 2 or 3;     -   each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆         haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆         alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆         alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,         —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R⁴ on         the same carbon optionally combine to form oxo, and two R⁴ on         different carbons optionally combine to form a —(C₀-C₄         alkylene)- bridge;     -   x is 0, 1, 2, 3 or 4;     -   J is absent, —C(O)—, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—, in which         R¹³ is selected from —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) and         —C(O)O—(C₁-C₄ alkyl);     -   the ring system denoted by “B” is absent, arylene,         heteroarylene,

-   -    wherein each of Y¹ and Y² is N, C or CH, provided that at least         one of Y¹ and Y² is N, p is 0, 1, 2, 3 or 4, q is 1, 2.3 or 4,         and the sum of p and q is 1, 2, 3, 4, 5 or 6, or

-   -    wherein Y¹ is N or C and Y² is N, C or CH, provided that at         least one of Y¹ and Y² is N, the ring system denoted by “C” is         an arylene or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2,         3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6;     -   T is H, —(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-R²³ in which R²³ is Het         or Ar and in which one or more non-adjacent carbons of the alkyl         is optionally replaced by —O— or —S—, —(C₀-C₆ alkyl)-L-R⁷,         —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆         alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰ or

-   -    wherein         -   Q is —O—(C₀-C₃ alkyl)-, —S(O)₂—, -L- or (C₀-C₃ alkyl)-, in             which each carbon of the —(C₀-C₃ alkyl)- is optionally and             independently substituted with one or two R¹⁶;         -   the ring system denoted by “A” is heteroaryl, aryl,             cycloalkyl or heterocycloalkyl;         -   each R⁵ is independently selected from —(C₁-C₆ alkyl),             —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,             —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,             —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆             alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃,             —SF₅, —NO₂ and —CN; and         -   y is 0, 1, 2, 3 or 4;     -   in which         -   each L is independently selected             -   from —NR⁹C(O)O—, —OC(O)NR⁹—, —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—,                 —SC(O)NR⁹—, —NR⁹C(O)—, —C(O)—NR⁹—, —NR⁹C(S)O—,                 —OC(S)NR⁹—, —NR⁹C(S)—NR⁹—, —NR⁹C(S)S—, —SC(S)NR⁹—,                 —NR⁹C(S)—, —C(S)NR⁹—, —SC(O)NR⁹—, —NR⁹C(S)—, —S(O)₀₋₂—,                 —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—,                 —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—,                 —SC(S)O—, —OC(S)S—, —NR⁹C(NR²)NR⁹—, —NR⁹SO₂—, —SO₂NR⁹—                 and —NR⁹SO₂NR⁹—,         -   each R⁶, R⁷, R⁸ and R¹⁰ is independently selected from H,             —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar,             —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca,             —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹—(C₀-C₆             alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆             alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆             alkyl),         -   each R⁹ is independently selected from —H, —(C₁-C₄ alkyl),             —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl),         -   each Ar is an optionally substituted aryl,         -   each Het is an optionally substituted heteroaryl,         -   each Cak is an optionally substituted cycloalkyl,         -   each Hca is an optionally substituted heterocycloalkyl, and         -   each alkyl is optionally substituted.

Also disclosed herein are pharmaceutical compositions. Examples of such compositions include those having at least one pharmaceutically acceptable carrier, diluent or excipient; and a compound, pharmaceutically acceptable salt, prodrug or N-oxide (or solvate or hydrate) disclosed herein.

Another aspect of the present disclosure includes methods for modulating metabolism in subjects. Accordingly, also disclosed are methods for treating metabolic disorders using the presently disclosed compounds and pharmaceutical compositions.

Another aspect of the present disclosure includes methods for modulating sphingolipid metabolism, for example modulating ceramide signalling in subjects. In one aspect, modulating sphingolipid metabolism includes modulating ceramidase activity, for example by up-regulating ceramidase function. Accordingly, also disclosed are methods for treating ceramide-linked diseases and disorders using the presently disclosed compounds and pharmaceutical compositions.

DETAILED DESCRIPTION

One aspect of the disclosure provides compounds having structural formula (I):

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), in which

-   -   0 or 1 of D¹, D² and D³ is N, with the others independently         being CH or C substituted by one of the w R³;     -   E is —R², —C(O)NR¹R², —NR¹R² or —NR¹C(O)R², in which R¹ and R²         together with the nitrogen to which they are bound form Hca, or         R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄         alkyl), and R² is —C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₁-C₃         alkyl)-O—Ar, —(C₁-C₃ alkyl)-O-Het, —(C₀-C₃ alkyl)-Het, —(C₀-C₃         alkyl)-Cak or —(C₀-C₃ alkyl)-Hca;     -   each R³ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆         haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆         alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆         alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,         —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN;     -   w is 0, 1, 2 or 3;     -   each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆         haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆         alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆         alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,         —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R⁴ on         the same carbon optionally combine to form oxo, and two R⁴ on         different carbons optionally combine to form a —(C₀-C₄         alkylene)- bridge;     -   x is 0, 1, 2, 3 or 4;     -   J is absent, —C(O)—, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—, in which         R¹³ is selected from —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) and         —C(O)O—(C₁-C₄ alkyl);     -   the ring system denoted by “B” is absent, arylene, heteroarylene

-   -    wherein each of Y¹ and Y² is N, C or CH, provided that at least         one of Y¹ and Y² is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4,         and the sum of p and q is 1, 2, 3, 4, 5 or 6, or

-   -    wherein Y¹ is N or C and Y² is N, C or CH, provided that at         least one of Y¹ and Y² is N, the ring system denoted by “C” is         an arylene or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2,         3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6;     -   T is H, —(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-R²³ in which R²³ is Het         or Ar and in which one or more non-adjacent carbons of the alkyl         is optionally replaced by —O— or —S—, —(C₀-C₆ alkyl)-L-R⁷,         —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆         alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰ or

-   -    wherein         -   Q is —O—(C₀-C₃ alkyl)-, —S(O)₂—, -L- or (C₀-C₃ alkyl)-, in             which each carbon of the —(C₀-C₃ alkyl)- is optionally and             independently substituted with one or two R¹⁶;         -   the ring system denoted by “A” is heteroaryl, aryl,             cycloalkyl or heterocycloalkyl;         -   each R⁵ is independently selected from —(C₁-C₆ alkyl),             —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,             —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,             —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆             alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃,             —SF₅, —NO₂ and —CN; and         -   y is 0, 1, 2, 3 or 4;     -   in which         -   each L is independently selected             -   from —NR⁹C(O)O—, —OC(O)NR⁹—, —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—,                 —SC(O)NR⁹—, —NR⁹C(O)—, —C(O)—NR⁹—, —NR⁹C(S)O—,                 —OC(S)NR⁹—, —NR⁹C(S)—NR⁹—, —NR⁹C(S)S—, —SC(S)NR⁹—,                 —NR⁹C(S)—, —C(S)NR⁹—, —SC(O)NR⁹—, —NR⁹C(S)—, —S(O)₀₋₂—,                 —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—,                 —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—,                 —SC(S)O—, —OC(S)S—, —NR⁹C(NR²)NR⁹—, —NR⁹SO₂—, —SO₂NR⁹—                 and —NR⁹SO₂NR⁹—,         -   each R⁶, R⁷, R⁸ and R¹⁰ is independently selected from H,             —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar,             —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca,             —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹—(C₀-C₆             alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆             alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆             alkyl),         -   each R⁹ is independently selected from —H, —(C₁-C₄ alkyl),             —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl),         -   each Ar is an optionally substituted aryl,         -   each Het is an optionally substituted heteroaryl,         -   each Cak is an optionally substituted cycloalkyl,         -   each Hca is an optionally substituted heterocycloalkyl, and         -   each alkyl is optionally substituted.

In certain embodiments of the presently disclosed compounds of structural formula (I) as described above, the compound has structural formula (II):

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), in which

-   -   E is —R², —C(O)NR¹R², —NR¹R², —NR¹C(O)R², in which R¹ and R²         together with the nitrogen to which they are bound form Hca, or         R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄         alkyl), and R² is —C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₀-C₃         alkyl)-Het, —(C₀-C₃ alkyl)-Cak or —(C₀-C₃ alkyl)-Hca;     -   each R³ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆         haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆         alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆         alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,         —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN;     -   w is 0, 1, 2 or 3;     -   each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆         haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆         alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆         alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,         —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R⁴ on         the same carbon optionally combine to form oxo;     -   x is 0, 1, 2, 3 or 4;     -   J is absent, —C(O)—, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—, in which         R¹³ is selected from —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) and         —C(O)O—(C₁-C₄ alkyl);     -   the ring system denoted by “B” is absent, arylene,         heteroarylene, or

-   -    wherein each of Y¹ and Y² is N, C or CH, provided that at least         one of Y¹ and Y² is N; p is 0, 1, 2, 3 or 4, q is 1, 2.3 or 4,         and the sum of p and q is 2, 3, 4, 5 or 6;     -   T is H, —(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-R²³ in which R²³ is Het         or Ar and in which one or more non-adjacent carbons of the alkyl         is optionally replaced by —O— or —S—, —(C₀-C₆ alkyl)-L-R⁷,         —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆         alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰ or

-   -    wherein         -   Q is —O—(C₀-C₃ alkyl)-, —S(O)₂—, -L- or (C₀-C₃ alkyl)-, in             which each carbon of the —(C₀-C₃ alkyl)- is optionally and             independently substituted with one or two R¹⁶;         -   the ring system denoted by “A” is heteroaryl, aryl,             cycloalkyl or heterocycloalkyl;         -   each R⁵ is independently selected from —(C₁-C₆ alkyl),             —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het,             —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,             —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆             alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂             and —CN; and         -   y is 0, 1, 2, 3 or 4;     -   in which         -   each L is independently selected             -   from —NR⁹C(O)O—, —OC(O)NR⁹—, —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—,                 —SC(O)NR⁹—, —NR⁹C(O)—, —C(O)—NR⁹—, —NR⁹C(S)O—,                 —OC(S)NR⁹—, —NR⁹C(S)—NR⁹—, —NR⁹C(S)S—, —SC(S)NR⁹—,                 —NR⁹C(S)—, —C(S)NR⁹—, —SC(O)NR⁹—, —NR⁹C(S)—, —S(O)₀₋₂—,                 —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—,                 —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—,                 —SC(S)O—, —OC(S)S—, —NR⁹C(NR²)NR⁹—, —NR⁹SO₂—, —SO₂NR⁹—                 and —NR⁹SO₂NR⁹—,         -   each R⁶, R⁷, R⁸ and R¹⁰ is independently selected from H,             —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar,             —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca,             —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹—(C₀-C₆             alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆             alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆             alkyl),         -   each R⁹ is independently selected from —H, —(C₁-C₄ alkyl),             —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl),         -   each Ar is an optionally substituted aryl,         -   each Het is an optionally substituted heteroaryl,         -   each Cak is an optionally substituted cycloalkyl,         -   each Hca is an optionally substituted heterocycloalkyl, and         -   each alkyl is optionally substituted.

In certain embodiments of the presently disclosed compounds of structural formula (I), the compound is not

-   5-(4-(4-cyanobenzyl)piperazine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide; -   N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide; -   N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)picolinamide -   (S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-fluorobenzyl)pyrrolidin-3-yl)picolinamide; -   (S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)picolinamide; -   (S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-cyanobenzyl)pyrrolidin-3-yl)picolinamide; -   N-(1-(4-chlorobenzyl)pyrrolidin-3-yl)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)picolinamide;     or -   5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)picolinamide.

In one embodiment, the presently disclosed compounds are not compounds disclosed in Darwish et al., International Patent Application no. PCT/US10/22411, filed Jan. 28, 2010, which is hereby incorporated by reference in its entirety.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, D¹, D² and D³ are independently CH or C substituted by one of the w R³. In other embodiments, D¹ is N and D² and D³ are independently CH or C substituted by one of the w R³. In other embodiments, D² is N and D¹ and D³ are independently CH or C substituted by one of the w R³. In other embodiments, D³ is N and D¹ and D² are independently CH or C substituted by one of the w R³.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, J is —C(O)—, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—, in which R¹³ is selected from —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl). In certain embodiments of the compounds of structural formula (I) and (II) as described above, R¹³ is H. In other embodiments. R¹³ is unsubstituted (C₁-C₄ alkyl). In certain embodiments of the compounds of structural formula (I) and (II) as described above, J is —C(O)—. In other embodiments, J is —NR¹³— (for example, —NH—). In still other embodiments, J is —NR¹³C(O)— (for example, —NHC(O)—). In other embodiments, J is —C(O)NR¹³— (for example, —C(O)NH—). In still other embodiments, J is absent.

In the presently disclosed compounds of structural formula (I) and (II) as described above, the ring system denoted by “B” is absent, arylene, heteroarylene,

in which each of Y¹ and Y² is N, C or CH, provided that at least one of Y¹ and Y² is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6,

wherein Y¹ is N or C and Y² is N, C or CH, provided that at least one of Y¹ and Y² is N, the ring system denoted by “C” is an arylene or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6.

For example, in certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, (for example, those described below with respect to structural formula (IV)), the ring system denoted by “B” is arylene or heteroarylene. In certain embodiments, the ring system denoted by “B” is arylene (for example, phenylene such as 1,4-phenylene). In other embodiments, the ring system denoted by “B” is heteroarylene (for example, 1H-pyrazolylene, 1H-1,2,3-triazolylene, pyridylene, furanylene or thienylene). In certain embodiments of the presently disclosed compounds of structural formula (I) as described above, the ring system denoted by “B” is monocyclic arylene or heteroarylene.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the ring system denoted by “B” is absent.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the ring system denoted by “B” is

wherein each of Y¹ and Y² is N, C or CH, provided that at least one of Y¹ and Y² is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 2, 3, 4, 5 or 6. For example, in certain embodiments, Y¹ is N and Y² is C or CH. (When Y¹ or Y² is C, it is substituted by one of the x R⁴.) In other embodiments, Y¹ is C or CH and Y² is N. In other embodiments, Y¹ is CF and Y² is N. In other embodiments, Y¹ and Y² are each N. In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, p is 1 and q is 2. For example, in one embodiment, the ring system denoted by “B” is a piperidine linked to the T moiety through its nitrogen atom. In another embodiment, the ring system denoted by “B” is a piperidine linked to the J moiety through its piperidine nitrogen. In another embodiment, the ring system denoted by “B” is a piperazine. In other embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, p is 1 and q is 1. For example, in certain embodiments, the ring system denoted by “B” is a pyrrolidine, for example, linked to the J moiety through its pyrrolidine nitrogen. In still other embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, p is 0 and q is 1. For example, in certain embodiments, the ring system denoted by “B” is an azetidine, for example, linked to the J moiety through its azetidine nitrogen.

In certain embodiments of the presently disclosed compounds of structural formula (I) as described above, the ring system denoted by “B” is

wherein Y¹ is N or C and Y² is N, C or CH, provided that at least one of Y¹ and Y² is N, the ring system denoted by “C” is an arylene or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6. For example, in certain embodiments, Y¹ is N and Y² is C or CH. (When Y² is C, it can be substituted by one of the x R⁴.) In other embodiments, Y¹ is C and Y² is N. In other embodiments, Y¹ and Y² are each N. In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, p is 1 and q is 2. In other embodiments of the presently disclosed compounds of structural formula (I) as described above, p is 1 and q is 1. The heteroarylene can be, for example, a pyridine, a pyrazine, a pyrimidine, a triazine, a pyrrole, a pyrazole, an imidazole, or a triazole. In one example, the ring system denoted by “B” is

In the presently disclosed compounds of structural formula (I) and (II) as described above, x, the number of substituents on the ring system denoted by “B”, is 0, 1, 2, 3 or 4. In one embodiment, x is 0, 1, 2 or 3. For example, in certain embodiments, x is 0. In other embodiments, x can be 1 or 2.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above (for example, when the ring system denoted by “B” is

two R⁴ groups combine to form an oxo. The oxo can be bound, for example, at the position alpha to a nitrogen atom of the ring system. In other embodiments, no two R⁴ groups combine to form an oxo.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above (for example, when the ring system denoted by “B” is

two R⁴ groups on different carbons combine to form a —(C₀-C₄ alkylene)- bridge. The alkylene bridge can form bicyclic system, for example, a [3.2.1] system, a [3.2.0] system, a [3.1.0] system, [2.2.2] system, a [2.2.1] system, a [2.1.1] system, a [2.2.0] system or a [2.1.0] system. For example, in one embodiment, ring system denoted by “B” is substituted with R⁴ groups to form

In certain embodiments the —(C₀-C₄ alkylene)- bridge is unsubstituted. In other embodiments, it is substituted only with one or more halogens.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above (for example, when the ring system denoted by “B” is

two R⁴ moieties (for example, on the same carbon) are (C₁-C₄ alkyl) (for example, methyl), as described below.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, when x is 4, not all four R⁴ groups are (C₁-C₆ alkyl).

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (for example, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R⁴ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, each R⁴ is independently halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl), and two R₄ optionally come together to form oxo. In certain embodiments, each R⁴ is independently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy, —SO₂Me, -halogen, —NO₂ or —CN, and two R₄ optionally come together to form oxo.

In the presently disclosed compounds of structural formula (I) and (II) as described above, E is —R², —C(O)NR¹R², —NR¹R² or —NR¹C(O)R², in which R¹ and R² together with the nitrogen to which they are bound form Hca, or R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄ alkyl); and R² is —C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₃ alkyl)-Cak or —(C₀-C₃ alkyl)-Hca. In certain embodiments, E is —C(O)NR¹R². In other embodiments, E is —NR¹R². In other embodiments, E is —R². In still other embodiments, E is —NR¹C(O)R².

In certain embodiments of the compounds of structural formula (I) and (II) as described above, R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄ alkyl); and R² is —C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₀-C₃ alkyl)-Het, —(C₀-C₃ alkyl)-Cak or —(C₀-C₃ alkyl)-Hca. In certain of the compounds of structural formula (I) as described above, R¹ is H. In other embodiments, R¹ is (C₁-C₄ alkyl), for example methyl, ethyl, n-propyl or isopropyl. In still other embodiments, R¹ is —C(O)—O—(C₁-C₄ alkyl), for example —C(O)OCH₃ or —C(O)—O-t-butyl. In certain embodiments, no alkyl of R¹ is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, any alkyl of R¹ is unsubstituted.

In certain of the compounds of structural formula (I) and (II) as described above, R² is —Hca. In certain embodiments, R² is an optionally-substituted monocyclic heterocycloalkyl. By way of example, such optionally substituted R² moieties include, without limitation, -(optionally-substituted azetidinyl), -(optionally-substituted pyrrolidinyl), -(optionally-substituted piperidinyl), -(optionally-substituted piperazinyl) or -(optionally-substituted azepanyl). For example, in one embodiment, R² can be -(optionally substituted piperidinyl) or -(optionally substituted pyrrolidinyl). In one embodiment, R² is -(optionally substituted piperidinyl). In another embodiment, R² is -(optionally substituted pyrrolidinyl). In another embodiment, R² is -(optionally substituted piperazinyl).

In certain particular embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, R² is -(optionally-substituted azetidin-3-yl), -(optionally substituted piperidin-4-yl), -(optionally substituted piperazin-4-yl), -(optionally substituted pyrrolidin-3-yl) or -(optionally-substituted azepan-4-yl). For example, in one embodiment, R² is -(optionally substituted piperidin-4-yl). In another embodiment, R² is -(optionally substituted pyrrolidin-3-yl). In another embodiment, R² is -(optionally substituted piperazin-4-yl).

In certain particular embodiments, when R² is -(optionally substituted piperidin-4-yl), it is unsubstituted at its 2- and 3-positions.

In other embodiments, when R² is -(optionally substituted piperidin-4-yl), it is substituted with F at a 3-position. For example, R² can be

in which the R group is a further substituent, for example, as described below. Such compounds can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and azepanyl R² moieties described above are substituted, for example, at their 1-positions. In certain alternative embodiments, they can be substituted at their 4-positions (e.g., when a piperidin-1-yl) or 3 positions (e.g., when a pyrrolidin-5-yl). For example, in one embodiment, R² is substituted (e.g., at its 1-position) with —(C₀-C₃ alkyl)-Ar or —(C₀-C₃ alkyl)-Het, for example -(unsubstituted C₀-C₃ alkyl)-Ar or -(unsubstituted C₀-C₃ alkyl)-Het. For example, in one particular embodiment, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., at its 1-position) with an optionally substituted benzyl or an optionally substituted phenyl. In another embodiment, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., at its 1-position) with a benzyl substituted with an electron withdrawing group; or a phenyl substituted with an electron withdrawing group. For example, the benzyl or phenyl can be substituted with an electron withdrawing group selected from the group consisting of halo, cyano, —(C₁-C₄ fluoroalkyl), —O—(C₁-C₄ fluoroalkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), —S(O)₂O—(C₀-C₄ alkyl), SF₅, NO₂ and —C(O)—Hca in which the Hca includes a nitrogen atom to which the —C(O)— is bound, in which no alkyl, fluoroalkyl or heterocycloalkyl is substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., at its 1-position) with an unsubstituted benzyl or an unsubstituted phenyl. In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., at its 1-position) with —CH(CH₃)Ar, CH(C(O)OCH₃)Ar or —C(CH₃)₂Ar.

In other embodiments of the compounds disclosed herein of structural formula (I) and (II) as described above, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., at its 1-position) with an optionally substituted pyridinylmethyl, an optionally substituted furanylmethyl, an optionally substituted thienylmethyl, an optionally substituted oxazolylmethyl, or an optionally substituted imidazolylmethyl. For example, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety can be substituted with an unsubstituted pyridinylmethyl, an unsubstituted furanylmethyl, an unsubstituted thienylmethyl, an unsubstituted oxazolylmethyl, or an unsubstituted imidazolylmethyl. In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R² moiety can be substituted with an pyridinylmethyl, furanylmethyl, thienylmethyl, oxazolylmethyl or imidazolylmethyl substituted with an electron withdrawing group as described above.

In certain embodiments of the compounds disclosed herein of structural formula (I) and (II) as described above, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., at its 1-position) with -L-Ar or -L-Het, in which Ar and Het can be, for example, as described above with reference to —(C₀-C₃ alkyl)-Ar or —(C₀-C₃ alkyl)-Het. In one such embodiment, L is —C(O)—NR⁹—, such as —C(O)—NH—. In other embodiments of the presently disclosed compounds of structural formula (I) as described above, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., at its 1-position) with —C(O)—O(C₀-C₆ alkyl), —C(O)-Het, —C(O)—Ar, —S(O)₂-Het, —S(O)₂—Ar or —S(O)₂—O(C₀-C₆ alkyl), in which Ar and Het can be, for example, as described above with reference to —(C₀-C₃ alkyl)-Ar or —(C₀-C₃ alkyl)-Het. In one embodiment, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., at its 1-position) with —C(O)-Het or —C(O)—Ar; in another embodiment, it is substituted (e.g., at its 1-position) with —S(O)₂-Het or —S(O)₂—Ar. For example, in certain embodiments, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., at its 1-position) with an optionally-substituted benzoyl (for example, substituted with an electron withdrawing group as described above); or with an optionally-substituted nicotinyl, isonicotinyl or picolinyl (for example, optionally substituted with an electron withdrawing group as described above). In other embodiments, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., at its 1-position) with an unsubstituted benzoyl; or an unsubstituted nicotinoyl, isonicotinoyl or picolinoyl.

In other embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., at its 1-position) with —(C₀-C₃ alkyl)-Cak, for example -(unsubstituted C₀-C₃ alkyl)-Cak (e.g., —CH₂-Cak) or —C(O)-Cak.

In one embodiment, R² is not an oxo-substituted heterocycloalkyl. In another embodiment, R² is not a tetramethyl-substituted heterocycloalkyl.

In certain embodiments of the compounds of structural formula (I) and (II) as described above (for example, those in which E is —C(O)NR¹R²), R¹ and R² together with the nitrogen to which they are bound form Hca. In such embodiments, Hca can be, for example, an optionally-substituted piperidinyl, an optionally-substituted pyrrolidinyl, or an optionally-substituted piperazinyl. When R¹ and R² together to form Hca, it can be defined and substituted as described above for R² wherein it is Hca.

In certain embodiments of the compounds of structural formula (I) and (II) as described above (for example, those in which E is —R², or —NR¹R²), R² is —C(O)Hca. In certain such embodiments, the Hca is linked to the —C(O)— through a nitrogen. In other such embodiments, the Hca can be linked to the —C(O)— through a carbon atom. The Hca can be defined and substituted, for example, as described above with respect to R² when it is Hca.

In certain embodiments of the compounds of structural formula (I) as described above (for example, those in which E is —R², —NR¹R² or —C(O)NR¹R²), R² is —(C₀-C₃ alkyl)-Ar or —(C₀-C₃ alkyl)-Het. For example, in certain embodiments, R² is Ar, in which the Ar can be, for example, monocyclic, such as optionally-substituted phenyl. In other embodiments, R² is —(C₁-C₃ alkyl)-(optionally-substituted phenyl), for example optionally-substituted benzyl. In other embodiments, R² is Het, in which the Het can be, for example, monocyclic, such as optionally-substituted pyridinyl or optionally-substituted 1H-pyrazolyl. In other embodiments of the compounds of structural formula (I) as described above (for example, those in which E is —C(O)NR¹R²), R² is —(C₀-C₃ alkyl)-Cak, in which the Cak can be, for example, monocyclic, such as optionally-substituted cyclohexyl. The aryl, heteroaryl or cycloalkyl of R² can be substituted, for example, as described above with reference to R² when it is Hca. For example, in certain embodiments, the aryl, heteroaryl or cycloalkyl of R² is substituted with —(C₀-C₃ alkyl)-Ar or —(C₀-C₃ alkyl)-Het, substituted as described above. In other embodiments, the aryl, heteroaryl or cycloalkyl of R² is substituted with —O—(C₀-C₃ alkyl)-Ar or —O—(C₀-C₃ alkyl)-Het. In other embodiments, the aryl, heteroaryl or cycloalkyl of R² is substituted with an optionally-substituted heterocycloalkyl, such as a morpholin-1-yl, a 4-methylpiperazin-1-yl, or a pyrrolidin-1-yl. The ring system of the R² moiety can be substituted at any position. For example, in certain embodiments, the ring of a monocyclic R² moiety is substituted at the 4-position, as counted from the attachment to the central pyridine, pyrazine, pyridazine or pyrimidine, or the nitrogen or carbonyl of the E moiety. In other embodiments, the ring of a monocyclic R² moiety is substituted at the 3-position, as counted from the attachment to the central pyridine, pyrazine, pyridazine or pyrimidine, or the nitrogen or carbonyl of the E moiety.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (III)

in which E is —R², —C(O)NR¹R², —NR¹R² or —NR¹C(O)R², in which R¹ and R² together with the nitrogen to which they are bound form Hca, or R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄ alkyl); and R² is —C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₀-C₃ alkyl)-Het, —(C₀-C₃ alkyl)-Cak or —(C₀-C₃ alkyl)-Hca. All other variables are as described above with reference to structural formulae (I) and (II). In certain such embodiments, E is R², —NR¹R² or —NR¹C(O)R². In certain embodiments of the compounds of structural formula (III), J is —C(O)—.

In certain embodiments of compounds of structural formulae (I)-(III) as described above, (for example, those in which E is —C(O)NR¹R²), when R² is Hca (for example, pyrrolidine or piperidine), it is substituted with at least one fluorine, and further optionally substituted, for example, as described below. In certain embodiments of compounds of structural formula (III) (for example, those in which E is —C(O)NR¹R²), when R² is Hca (for example, pyrolidine or piperazine), it is substituted (for example, at the nitrogen) with —C(O)—R²², —S(O)₂—R²², —C(O)-Cak, —CH₂-Cak, —CH(CH₃)—R²², —C(CH₃)₂—R²², —CH(C(O)—O(C₁-C₄ alkyl))Het, in which R²² is Ar or Het, and further optionally substituted, for example, as described below.

In certain embodiments of the compounds of structural formulae (I)-(III) as described above, (for example, those in which E is —C(O)NR¹R²), R¹ and R² together with the nitrogen to which they are bound form Hca, as described below. For example, R¹ and R² can together to form an optionally substituted piperazine or an optionally-substituted pyrrolidine, as described below. In other embodiments, R¹ and R² together with the nitrogen to which they are bound form an optionally-substituted spirocyclic heterocycloalkyl (for example, 2,8-diazaspiro[4.5]decanyl), as described below.

In certain embodiments of the compounds of structural formulae (I)-(III) as described above, (for example, those in which E is —C(O)NR¹Hca), T is H, —C(O)—(C₁-C₆ alkyl) or (C₁-C₆ alkyl), for example, as described below. In other embodiments of the compounds of structural formula (III) (for example, those in which E is —C(O)NR¹Hca), T is —C(CH₃)₂Ar, —CH₂-Het, -Het, —CH₂-Cak or Hca, for example, as described below. In other embodiments of the compounds of structural formula (III) (for example, those in which E is —C(O)NR¹Hca), T is

in which Q is —C(O)— or —S(O)₂—, for example, as described below.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (IV)

in which J is absent, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—; and the ring system denoted by “B” is arylene, heteroarylene, or absent, and all other variables are as described with respect to structural formulae (I)-(III). For example, in certain embodiments of the compounds of structural formula (IV) as described above, J is absent. In other embodiments, J is —NR¹³—, such as —NH—. In other embodiments, J is —NR¹³C(O)—, such as —NHC(O)—. In certain embodiments, the ring system denoted by “B” is arylene, such as phenylene); or heteroarylene, such as 1H-pyrazolylene, 1H-1,2,3-triazolylene), with particular examples being described below. In other embodiments, the ring system denoted by “B” is absent, with particular examples being described below. In certain embodiments of the compounds of structural formula (IV), (for example, those in which E is —C(O)NR¹R²), R² is Hca, such as piperidinyl, with particular examples being described below.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (V)

in which the variables are as described above with reference to structural formulae (I)-(III). In certain embodiments of the compounds of structural formula (V), R² is Hca (for example, pyrrolidine or piperidine), for example, described below. In other embodiments of the compounds of structural formula (IV), R² is Cak, such as cyclohexyl, for example, described below.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (VI)

in which Y is N, C, CF or CH, and all other variables are as described above with reference to structural formulae (I)-(III). For example, in certain embodiments, Y is N. In other embodiments, Y is CF or CH. In certain embodiments of the compounds of structural formula (VI), p is 1 and q is 2. In other embodiments (for example, when Y is C, CF or CH), q is 1 and p is 1. In certain embodiments of the compounds of structural formula (VI), R² is Hca, such as pyrrolidine or piperidine.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (VII)

in which J is absent, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—, and all other variables are as described above with reference to structural formulae (I)(III). For example, in one embodiment, J is —NR¹³—C(O)—. In other embodiments, J is —NR¹³—. In certain embodiments of the compounds of structural formula (VII), p is 1 and q is 2. In other embodiments, q is 1 and p is 1. In other embodiments (for example, when Y is C, CF or CH), q is 1 and p is 0. In certain embodiments of the compounds of structural formula (VII), R² is Hca, such as pyrrolidine or piperidine, particular examples of which are further described below.

In certain embodiments of the presently disclosed compounds of structural formula (I) and (II) as described above, the compound has structural formula (VIII)

in which the variables are as described above with reference to structural formulae (I)-(III). In certain embodiments of the compounds of structural formula (VIII), p is 1 and q is 2. In other embodiments, q is 1 and p is 1. In other embodiments (for example, when Y is C, CF or CH), q is 1 and p is 0. In certain embodiments of the compounds of structural formula (VIII), R² is Hca.

In certain embodiments of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, T is

In such embodiments, Q is —O—(C₀-C₃ alkyl)-, —S(O)₂—, L or —(C₀-C₃ alkyl)- in which each carbon of the (C₀-C₃ alkyl) is optionally and independently substituted with one or two R¹⁶, in which each R¹⁶ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and optionally two of R¹⁶ on the same carbon combine to form oxo. In certain embodiments, each R¹⁶ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (for example, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R¹⁶ on the same carbon optionally combine to form an oxo, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₃ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in particular compounds, each R¹⁶ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R¹⁶ on the same carbon optionally combine to form an oxo, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, each R¹⁶ is independently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy, —SO₂Me, -halogen, —NO₂, N₃, —SF₅, or —CN, and two R¹⁶ optionally come together to form oxo. In certain embodiments, Q has at most one R¹⁶ or an oxo substituted thereon. Q can be, for example, an unsubstituted —(C₀-C₃ alkyl)- (for example, a single bond, —CH₂— or —CH₂—CH₂—). In other embodiments, Q is a (C₁-C₃ alkyl) having as its only substitution a single oxo group. For example, in certain embodiments of the compounds of structural formulae (I)-(VII) as described above, Q is —CH₂—; —CH₂CH₂—; —OCH₂CH₂—; O; a single bond; —S(O)₂—; —C(O)—; —CHF—; —CH(OH)—, —C(CH₃)₂—, or —CH(CH₃)—.

In certain embodiments of the compounds of structural formulae (I)-(VIII) as described above, T is

in which Q is —C(O)— or —S(O)₂—. In other embodiments, T is

in which Q is —C(CH₃)₂—, —CH₂CH₂—, —CH(CH₃)—, —CH(OH)— or —CHF—.

In certain embodiments of the compounds of structural formulae (I)-(VIII) as described above (for example, those in which T is not bound to a nitrogen), T is

in which Q is O.

In certain embodiments of the compounds of structural formulae (I)-(VIII) as described above (for example, those in which the ring system denoted by “B” is absent). T is

in which Q is —O—(C₁-C₃ alkyl)-, for example, —OCH₂— or —OCH₂CH₂—.

The number of substituents, y, on the ring system denoted by “A”, is 0, 1, 2, 3 or 4. For example, in some embodiments of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, y is 0, 1, 2 or 3, such as 1. In one embodiment, y is not zero and at least one R⁵ is halo, cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), —N₃, —SF₅, NO₂ or —C(O)—Hca wherein the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, and wherein no alkyl, haloalkyl or heterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.

In certain embodiments of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, each R⁵ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (for example, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃, —SF₅, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (for example, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R⁵ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃, —SF₅, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, each R⁵ is independently halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl). In certain embodiments, each R⁵ is independently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy, —SO₂Me, -halogen, —NO₂, N₃, —SF₅, or —CN.

In one embodiment of the compounds of structural formulae (I)-(VIII) as described above, y is 0. In another embodiment, y is 1. In another embodiment, y is 2.

In the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl or heterocycloalkyl. For example, in one embodiment, the ring system denoted by “A” is an aryl or a heteroaryl. The ring system denoted by “A” can be, for example, a monocyclic aryl or heteroaryl. In one embodiment, when the “A” ring system is aryl, Q is a —(C₀-C₃ alkyl)- optionally substituted with oxo, and optionally substituted with one or more R¹⁶. For example, Q can be a —(C₁-C₃ alkyl)- having its only substitution a single oxo, or an unsubstituted —(C₀-C₃ alkyl)-. In certain embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —CH₂—; —CH₂CH₂—; a single bond; —S(O)₂—; —C(O)—; or —CH(CH₃)—. In other embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —CF—, —CH(OH)— or —C(CH₃)₂—. In other embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —O—, —OCH₂— or —OCH₂CH₂—.

For example, in certain embodiments of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the ring system denoted by “A” is monocyclic aryl, such as phenyl. In one embodiment, y is 1 and R⁵ is attached to the phenyl in the para position relative to Q. In one embodiment, y is 1 and R⁵ is attached to the phenyl in the meta position relative to Q. In certain embodiments, y is 1 and R⁵ is selected from the group consisting of halo, cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO and —C(O)—Hca in which the Hca contains a ring nitrogen atom through which it is bound to the —C(O)—, and in which no (C₀-C₄ alkyl) or (C₁-C₄ alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. R⁵ can be, for example, —Cl, —F, cyano, —N₃, SF₅, —C(O)CH₃, —C(O)OH, —C(O)NH₂, methoxy, trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy. In another embodiment, the

moiety is a 3,4-dihalophenyl, a 3,5-dihalophenyl, a 3-cyano-5-methoxyphenyl, a 4-cyano-3-halophenyl, or a 3-halo-4-methoxyphenyl.

In another embodiment of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the ring system denoted by “A” is a heteroaryl. For example, in certain embodiments, the ring system denoted by “A” is a pyridyl, a thienyl, or a furanyl. In another embodiment, the ring system denoted by “A” is an isoxazolyl. In one embodiment, when the “A” ring system is heteroaryl, Q is a —(C₀-C₃ alkyl)- optionally substituted with oxo, and optionally substituted with one or more R¹⁶. For example, Q can be a —(C₁-C₃ alkyl)- having its only substitution a single oxo, or an unsubstituted —(C₀-C₃ alkyl)-. In certain embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —CH₂—; a single bond; —S(O)₂—; —C(O)—; or —CH(CH₃)—. In other embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —O—, —CF—, —CH(OH)— or —C(CH₃)₂—. In other embodiments, the ring system denoted by “A” is an aryl or a heteroaryl and Q is —O—, —OCH₂— or —OCH₂CH₂—.

In another embodiment of the presently disclosed compounds of formulae (I)-(VIII) as described above, the ring system denoted by “A” is a heterocycloalkyl. For example, in certain embodiments, the ring system denoted by “A” is a tetrahydro-2H-pyranyl or a morpholino. In one such embodiment, when the “A” ring system is a heterocycloalkyl, Q is a single bond. In another such embodiment, Q is —CH₂— or —C(O)—. In another such embodiment, Q is —O—, —OCH₂— or —OCH₂CH₂—.

In another embodiment of the presently disclosed compounds of formulae (I)-(VIII) as described above, the ring system denoted by “A” is a cycloalkyl. For example, in certain embodiments, the ring system denoted by “A” is a cyclohexyl. In one such embodiment, when the “A” ring system is a cycloalkyl, Q is —CH₂— or —C(O)—. In another such embodiment, Q is a single bond. In another such embodiment, Q is —O—, —OCH₂— or —OCH₂CH₂—.

In certain embodiments of the compounds of formulae (I)-(VIII) as described above, T is H, —(C₁-C₆ alkyl) or —C(O(C₁-C₆ alkyl). In certain such embodiments, the alkyl moieties of T are unsubstituted. In other such embodiments, the alkyl moieties of T are optionally substituted as described below. For example, in certain embodiments, T is H, isopropropyl, or —C(O)-t-butyl.

In certain embodiments of the compounds of formulae (I)-(VIII) as described above, T is —C(CH₃)₂Ar, —CH₂-Het, -Het, —CH₂-Cak or -Hca. The -Ar, -Het, -Cak and -Hca moieties can, for example, be substituted with y R⁵ moieties, as described above with reference to the ring system denoted by “A”.

In certain embodiments of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the T moiety is selected from the group consisting of

monocyclic heterocycloalkyl (for example, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl) substituted with 0, 1 or 2 R³⁰, monocyclic heteroaryl (for example, pyridyl, isoxazolyl, oxazolyl, pyrrolyl, thienyl) substituted with 0, 1 or 2 R³⁰; monocyclic heteroarylmethyl- (for example, pyridylmethyl, isoxazolylmethyl, oxazolylmethyl, pyrrolylmethyl, thienylmethyl), in which the heteroaryl is substituted with 0, 1 or 2 R³⁰; or monocyclic heteroaryloxy- (for example, pyridyloxy, isoxazolyloxy, oxazolyloxy, pyrrolyloxy, thienyloxy), in which the heteroaryl is substituted with 0, 1 or 2 R³⁰; in which each R³⁰ is independently selected from halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl). In certain embodiments, no R³³ is substituted on the ring of the T moiety. In other embodiments, one R is substituted on the ring of the T moiety, for example, at a para-position of a phenyl, a meta-position of a phenyl, or at a 3- or 4-position of a heteroaryl or heterocycloalkyl (as counted from the attachment point of the ring system denoted by “B”). Certain particular identities of the T moiety will be found by the person of skill in the art in the compounds described below with respect to Table 1. Those of skill in the art will understand that combinations of such T moieties with other subcombinations of features disclosed herein is specifically contemplated.

For example, in certain embodiments of the compounds of formulae (I)-(VIII) as described above, the T moiety is selected from

heterocycloalkyl optionally substituted by alkyl and/or halogen, -Q-heteroaryl optionally substituted by unsubstituted (C₁-C₄ alkyl) and/or halogen, H, C(O)tBu and isopropyl, in which each X is independently F, Cl or Br (preferably F or Cl), each R³³ is unsubstituted (C₁-C₄ alkyl), unsubstituted (C₁-C₄ haloalkyl) or cycloalkyl optionally substituted with unsubstituted alkyl, unsubstituted (C₁-C₄ alkyl), unsubstituted (C₁-C₄ haloalkyl) or cycloalkyl optionally substituted with unsubstituted alkyl, and each R³⁵ is heterocycloalkyl, optionally substituted with unsubstituted alkyl. In certain such embodiments, Q is a single bond, —CH₂—, —CH₂O—, —OCH₂CH₂—, —CH₂CH₂—, —O—, —CHF—, —CH(CH₃)—, —C(CH₃)₂—, —CH(OH)—, —CH(COOMe)-, —CH(COOEt)-, —C(O)— or —S(O)₂—.

In one embodiment of the presently disclosed compounds of structural formulae (I)-(VII) as described above, the compound has structural formula (IX):

in which the variables are defined as described above with reference to any of structural formulae (I)-(VIII).

In another embodiment of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the compound has structural formula (X):

in which the variables are defined as described above with reference to any of structural formulae (I)-(VIII). For example, in certain embodiments, R² can be

in which the R group is a further substituent, for example, as described herein.

In another embodiment of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the compound has structural formula (XI):

in which one of X¹, X², X³ and X⁴ are N, and the others are carbons (for example, independently CH or C substituted with one of the w R³ groups), and all other variables are defined as described above with reference to any of structural formulae (I)-(VIII). For example, in one embodiment, X¹ is N and X², X³ and X⁴ are carbons. In another embodiment. X² is N and X¹, X³ and X⁴ are carbons. In another embodiment, X³ is N and X¹, X² and X⁴ are carbons. In another embodiment, X⁴ is N and X¹, X² and X³ are carbons.

In another embodiment of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the compound has structural formula (XII):

in which the variables are defined as described above with reference to any of structural formulae (I)-(VIII).

In another embodiment of the presently disclosed compounds of structural formulae (I)-(VIII) as described above, the compound has structural formula (XIII):

in which the variables are defined as described above with reference to any of structural formulae (I)-(VIII).

In the compounds of any of structural formulae (I)-(XIII) as described above, w, the number of substituents on the central pyridine, pyridazine, pyrazine or pyrimidine, is 0, 1, 2 or 3. For example, in one embodiment, w is 0, 1 or 2. In another embodiment, w is 0. In other embodiments, w is at least 1, and at least one R³ is selected from the group consisting of halo, cyano, —(C₁-C₄ fluoroalkyl), —O—(C₁-C₄ fluoroalkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), —S(O)CO—(C₀-C₄ alkyl), NO and —C(O)—Hca in which the Hca includes a nitrogen atom to which the —C(O)— is bound, in which no alkyl, fluoroalkyl or heterocycloalkyl is substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. For example, in certain embodiments, at least one R³ is halo (for example, chloro) or —(C₁-C₄ alkyl) (for example, methyl, ethyl or propyl). In certain embodiments, an R³ is substituted on the central pyridine, pyrazine, pyridazine or pyrimidine in the meta position relative to the J moiety.

In certain embodiments of the compounds of any of structural formulae (I)-(XIII) as described above, each R³ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (for example, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO and —CN, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO and —CN, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in certain embodiments, each R³ is halo (for example, chloro) or —(C₁-C₄ alkyl) (for example, methyl, ethyl or propyl). In certain embodiments, each R³ is independently halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl). In certain embodiments, each R³ is independently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy, —SO₂Me, -halogen, —NO₂ or —CN.

In certain embodiments of the compounds of any of structural formulae (I)-(XIII) as described above, w is at least one, and at least one R³ is —NR⁸R⁹. For example, in one embodiment, w is 1. In certain such embodiments, an R³ is substituted on the central pyridine, pyrazine, pyridazine or pyrimidine in the meta position relative to the J moiety.

In other embodiments of the compounds of any of structural formulae (I)-(XIII) as described above, w is at least one, and at least one R³ is —(C₀-C₃ alkyl)-Y¹—(C₁-C₃ alkyl)-Y²—(C₀-C₃ alkyl), in which each of Y¹ and Y² is independently L, —O—, —S— or —NR⁹—. For example, in one embodiment, w is 1. In certain such embodiments, R³ is substituted on the central pyridine, pyrazine, pyridazine or pyrimidine in the meta position relative to the J moiety. In one particular embodiment, R³ is —CH₂—N(CH₃)—CH₂—C(O)—OCH₃.

In certain embodiments of the presently disclosed compounds of structural formulae (I)-(XIII) as described above, the compound has the structural formula (XIV):

in which E¹ is absent, —C(O)—, —C(O)NR¹— or —NR¹C(O)—; z is 0 or 1; Y³ is N, C or CH and Y⁴ is N, C or CH; Q and G are each independently a single bond, —CH₂—, —C(H)(R¹⁶)—, —C(R¹⁶)₂—, —CH₂CH₂—, L (for example, —C(O)—NR⁹— or —NR⁹—C(O)—), -L-C(R¹⁶)₂—, —O—(C₀-C₃ alkyl)- in which the (C₀-C₃ alkyl) is bound to the R¹⁷ moiety or the ring system denoted by “A”, or —S(O)₂—; v is 0, 1, 2, 3 or 4; each R¹⁵ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R¹⁵ on the same carbon optionally combine to form oxo; and R¹⁷ is Het or Ar, and all other variables are defined as described above with reference to any of structural formula (I)-(XIII).

In certain embodiments of the presently disclosed compounds of structural formula (XIV) as described above (for example, those in which E¹ is —C(O)— or absent, Y³ is N and Y⁴ is N. In other embodiments, (for example, those in which E¹ is —C(O)—NR¹—), Y³ is C or CH and Y⁴ is N. In other embodiments, Y³ is N and Y⁴ is C or CH. In other embodiments, Y is C or CH and Y⁴ is C or CH; in such embodiments, the E¹ and G moieties can be disposed, for example, cis to one another on the cycloalkyl ring. In certain embodiments of the presently disclosed compounds of structural formula (XIV) as described above, z is 1. In other embodiments, z is 0.

In certain embodiments of the presently disclosed compounds of structural formulae (I)-(XIV) as described above, D¹, D² and D³ are all CH or C substituted by one of the w R³, and the R² moiety is an optionally-substituted piperidine. For example, in one embodiment, a compound has structural formula (XV):

in which all variables are and all as described above with respect to any of structural formulae (I)-(XIV). In one such embodiment, v is 0.

In other embodiments of compounds according to structural formula (XV), one of the R¹⁵ is F. For example, the F can be substituted at the carbon alpha to the E¹ moiety. Accordingly, in certain embodiments, a compound has structural formula (XVI):

in which v is 0, 1, 2 or 3 and all other variables are as described above with respect to any of structural formulae (I)-(XIV). In certain such embodiments, v is 0. In one embodiment, the E¹ moiety and the F are disposed in a cis relationship to one another. In other embodiment, the E¹ moeity and the F are disposed in a trans relationship to one another. For example, the compound of structural formula (XVI) can be provided as any of the four diastereomers of structural formulae (XVII)-(XX):

in which v is 0, 1, 2 or 3 (e.g., 0), and all other variables are and all as described above with respect to any of structural formulae (I)-(XVI). Compounds can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form, for example, as one of the compounds of structural formulae (XVII)-(XX).

In certain embodiments of the compounds of structural formulae (XV)-(XX), the compound has structural formula (XXI):

in which all variables are as described above with respect to any of structural formulae (I)-(XX). For example, the

moiety can be selected from

in which the G-R¹⁷ group is as described herein. Such compounds can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form.

In the compounds of structural formulae (XV)-(XXI), the regiochemistry around the central pyridine can be as described with respect to any of claims (IX)-(XI). Moreover, the E¹ moiety of any such compounds can be absent, —C(O)—, —C(O)NR¹— or —NR¹C(O)—. In one such embodiment, a compound of any of structural formula (XV)-(XXI) is of structural formula (XXII):

in which all variables are as described above with respect to any of structural formulae (I)-(XXI). For example, the

moiety can be selected from

in which the G-R¹⁷ group is as described herein.

In certain embodiments of the compounds according to structural formula (XV)-(XXII), the ring denoted by “B” is

In certain such embodiments, Y² is N and Y¹ is CH or C substituted by one of the x R⁴. In other such embodiments, both Y¹ and Y² are N. For example, in certain embodiments, compounds according to structural formulae (XV)-(XXII) have structural formula (XXIII):

in which in which all variables are as described above with respect to any of structural formulae (I)-(XXII). In one embodiment, Y¹ is N. In another embodiment. Y¹ is CH, or is C substituted by one of the x R⁴. For example, in certain embodiments, compounds have one of structural formulae (XXIV)-(XXIX):

in which in which all variables are as described above with respect to any of structural formulae (I)-(XXII). In certain embodiments of the compounds of structural formulae (XXIV)-(XXIX), Y¹ is CH or C substituted by one of the x R⁴. In certain embodiments of the compounds of structural formulae (XXIV)-(XXIX), w is 0. In other such embodiments, x is 0. In still other such embodiments, both w and x are 0. In any such embodiments, R¹ can be, for example, H, or unsubstituted (C₁-C₄ alkyl) such as methyl. Compounds according to structural formulae (XXVI)-(XXIX) can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form.

In the compounds of structural formulae (XV)-(XXIX) as described above, G and Q can be as described above with reference to structural formulae (I)-(XIV). For example, in certain embodiments, G is CH₂, CO, or SO₂. In certain embodiments, Q is CH₂, CO, SO₂ or O.

In the compounds of structural formulae (XV)-(XXIX) as described above, R¹⁷ and T can be as described above with reference to structural formulae (I)-(XIV). For example, in certain embodiments, R¹⁷ is an optionally substituted phenyl, for example, substituted with 0-2 R³⁰ groups as described above. In other embodiments, R¹⁷ is an optionally substituted heteroaryl, for example, substituted with 0-2 R³⁰ groups as described above. In certain embodiments, T is

in which Q is as described above. The ring system denoted by A and its optional R⁵ substituents can be, for example, phenyl substituted by 0-2 R³⁰ groups as described above. In other embodiments, ring system denoted by A and its optional R⁵ substituents are heteroaryl, for example, substituted with 0-2 R³⁰ groups as described above.

As examples, in certain embodiments, the compounds have one of structural formulae (XXX)-(XXXV):

in which Q, G, R¹ and R³⁰ are as described above with reference to structural formulae (I)-(XXIX). In certain such embodiments, R¹ is H. In certain embodiments, G is CH₂, CO, or SO₂. In certain embodiments, Q is CH₂, CO, SO₂ or O. Compounds according to structural formulae (XXX)-(XXXV) can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form.

In other embodiments of the presently disclosed compounds of structural formulae (I)-(XIII) as described above, the compound has the structural formula (XXXVI):

in which the ring system denoted by “C” is a monocyclic arylene or heteroarylene, or a monocyclic arylene fused to a heterocycloalkyl, and all other variables are as defined above with respect to any of structural formulae (I)-(XIV). For example, in certain embodiments, the ring system denoted by “C” is a phenylene, for example, a 1,4-phenylene. In other embodiments, the ring system denoted by “C” is a monocyclic heteroarylene, such as a pyridylene (for example, a 2,5-pyridylene); a 1,3-pyrazolylene (for example, a 1,3-pyrazolylene); a furanylene (for example, a 2,4-furanylene); or a thienylene (for example, a 2,4-thienylene). In other embodiments, the ring system denoted by “C” is a 1,2,3,4-tetrahydroisoquinolinylene (for example, a 1,2,3,4-tetrahydroisoquinolin-2,6-ylene).

In other embodiments of the presently disclosed compounds of structural formulae (I)-(XIII) as described above, the compound has the structural formula (XVI):

in which z1 is 0 or 1; z2 is 0 or 1; Y⁵ is N, C or CH; Y⁶ is N, C or CH; each of the v R¹⁵ can be disposed either spiro-fused ring; and all other variables are as defined above with respect to any of structural formulae (I)-(XIV).

In certain embodiments of the presently disclosed compounds of structural formula (XXXVII) as described above (for example, those in which E¹ is —C(O)— or absent), Y⁵ is N and Y⁶ is N. In other embodiments, (for example, those in which E¹ is —C(O)—NR¹—). Y⁵ is C or CH and Y⁶ is N. In other embodiments, Y⁵ is N and Y⁶ is C or CH. In other embodiments, Y⁵ is C or CH and Y⁶ is C or CH. In certain embodiments of the presently disclosed compounds of structural formula (XXXVII) as described above, z1 is 1 and z2 is 0. In other embodiments, z1 is 0 and z2 is 1.

In one embodiment of the compounds of structural formula (XIV)-(XXXVII) as described above. Q is a single bond. In another embodiment, Q is —CH₂—. In other embodiments, Q is —C(O)— or —S(O)₂—. In other embodiments, Q is —NH—C(O)— or —CH₂—NH—C(O)—. In other embodiments, Q is —C(CH₃)₂—, —CH₂CH₂—, —CH(CH₃)—, —CH(OH)— or —CHF—. In other embodiments, Q is —O—. In other embodiments, Q is —CH₂O— or —OCH₂CH₂—. In other embodiments, Q is —CH(COOMe)- or —CH(COOEt)-.

In one embodiment of the compounds of structural formula (XIV)-(XXXVII) as described above, G is —CH₂—. In other embodiments, G is —C(O)— or —S(O)₂—. In other embodiments, G is —CH(CH₃)— or —C(CH₃)₂—. In other embodiments. G is —O—. In other embodiments, G is —C(O)—NH— or —C(O)—NH—CH₂—. In other embodiments, G is —CH₂CH₂—. In other embodiments, G is a single bond. In other embodiments, G is —O—. In other embodiments. G is —OCH₂— or —CH₂CH₂O—. In other embodiments, G is —CH(COOMe)- or —CH(COOEt)-.

In the presently disclosed compounds of structural formulae (XIV)-(XXXVII) as described above, the above-described Q and G moieties can be combined in any possible combination. For example, in one embodiment, Q is a single bond and G is —CH₂— or —C(O)—. In another embodiment, Q is —CH₂— or —C(O)— and G is a single bond. In yet another embodiment. Q is —CH₂— or —C(O)— and G is —CH₂— or —C(O)—.

In certain embodiments of the compounds of structural formulae (XIV)-(XXXVII) as described above, the ring system denoted by “A” is aryl or heteroaryl, as described above. In one embodiment, the ring system denoted by “A” is substituted with one or more electron-withdrawing groups as described above. In another embodiment, R¹⁷ is substituted with one or more electron-withdrawing groups as described above. In certain embodiments, the ring system denoted by “A”, R¹⁷ or both are not substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. In certain embodiments, the azacycloalkyl to which -G-R¹⁷ is bound is a piperidinyl; in other embodiments, it is a pyrrolidinyl.

In the presently disclosed compounds of structural formulae (XIV)-(XXXVII) as described above, v is 0, 1, 2, 3 or 4. In one embodiment, v is 0, 1, 2 or 3. For example, v can be 0, or can be 1 or 2.

In certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XXXVII) as described above, two R¹⁵ groups combine to form an oxo. The oxo can be bound, for example, at the position alpha relative to the nitrogen of an azacycloalkyl ring. In other embodiments, no two R¹⁵ groups combine to form an oxo.

In certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XXXVII) as described above, v is at least 1 (for example, 1) and at least one R¹⁵ is F. In certain embodiments, the F can be, for example, disposed at a position alpha to the E¹ moiety. When the F and E¹ are both disposed on saturated carbons, they can be disposed in a cis relationship with respect to one another. For example, in certain embodiments, a compound has structural formula (XXXVIII)

in which Y⁴ is N or CH and all variables are defined as described above with respect to structural formulae (I)-(XIV). In other embodiments, a compound has structural formula (XXXIX)

in which Y⁴ is N or CH and all variables are defined as described above with respect to structural formulae (I)-(XIV). In other embodiments, when the F and E¹ are both disposed on saturated carbons, they can be disposed in a trans relationship with respect to one another. For example, in one embodiment, a compound has structural formula (XL)

in which Y⁴ is N or CH and all variables are defined as described above with respect to structural formulae (I)-(XIV). In another embodiment, a compound has structural formula (XLI)

in which Y⁴ is N or CH and all variables are defined as described above with respect to structural formulae (I)-(XIV). Compounds according to structural formulae (XXXVIII)-(XLI) can be provided as mixtures of diastereomers or enantiomers, or in diastereomerically and/or enantiomerically enriched form. In certain embodiments, the compound is provided in substantially diastereomerically pure form, for example, as substantially diastereomerically pure cis compound, or diastereomerically pure trans compound. In certain embodiments, a compound is provided in substantially enantiomerically pure form.

In certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XLI) as described above, when v is 4, not all four R¹⁵ moieties are (C₁-C₆ alkyl).

In certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XLI) as described above, each R¹⁵ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (for example, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN and two R¹⁵ on the same carbon optionally combine to form oxo, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, each R¹⁵ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN and two R¹⁵ on the same carbon optionally combine to form oxo, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, each R¹⁵ is independently halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl). C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₈ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₈ alkyl), and two R₄ optionally come together to form oxo. In certain embodiments, each R¹⁵ is independently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy, —SO₂Me, -halogen, —NO₂, N₃, —SF₅, or —CN, and two R¹⁵ on the same carbon optionally combine to form oxo. In some embodiments, one R¹⁵ is —C(O)NR⁹R⁷, which can be bound, for example, at a position alpha relative to the piperidine nitrogen, or at the position linked to the E¹ moiety.

In certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XLI) as described above, R¹⁷ is an unsubstituted aryl or heteroaryl. In other embodiments, the R¹⁷Ar or Het is substituted with 1, 2 or 3 substituents independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (for example, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₃ alkyl)-L-(C₀-C₃ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. For example, in one embodiment, the R¹⁷Ar or Het is substituted with 1, 2 or 3 substituents independently selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, R¹⁷ is substituted with 1, 2 or 3 substituents selected from halo, cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and —C(O)—Hca in which no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. In certain embodiments, R¹⁷ is substituted with 1, 2 or 3 substituents selected from halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₈ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl), and two R₄ optionally come together to form oxo. In certain embodiments, each R¹⁷ is substituted with 1, 2 or 3 substituents selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy, —SO₂Me, -halogen, —NO₂, N₃, —SF₅, or —CN. R⁷ can be substituted with, for example, one such substituent, or two such substituents.

In certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XLI) as described above, at least one of R¹⁷ and the ring system denoted by “A” is substituted with —C(O)NR²⁷R²⁹, in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (for example, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₈ alkyl), in which no heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R²⁹ is —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl) is substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, or R²⁷ and R²⁹ together with the nitrogen to which they are bound form Hca (for example, morpholino, piperazinyl, pyrrolidinyl or piperidinyl). In certain embodiments, heterocycloalkyl, alkyl or haloalkyl groups of R²⁷ and R²⁹ are substituted with 1, 2 or 3 substituents selected from halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₈ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl), and two R₄ optionally come together to form oxo. In certain embodiments, the heterocycloalkyl, alkyl or haloalkyl groups of R²⁷ and R²⁹ are optionally substituted with acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy, —SO₂Me, -halogen, —NO₂, N₃, —SF₅, or —CN. In one embodiment, R²⁷ and R²⁹ are both H. In another embodiment, R²⁷ is CH₃ and R²⁹ is H.

In certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XLI) as described above, the -G-R¹⁷ moiety is selected from the group consisting of

monocyclic heterocycloalkyl (for example, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl) substituted with 0, 1 or 2 R³⁰, monocyclic heteroaryl (for example, pyridyl, isoxazolyl, oxazolyl, pyrrolyl, thienyl) substituted with 0, 1 or 2 R³⁰; monocyclic heteroarylmethyl- (for example, pyridylmethyl, isoxazolylmethyl, oxazolylmethyl, pyrrolylmethyl, thienylmethyl), in which the heteroaryl is substituted with 0, 1 or 2 R³⁰; or monocyclic heteroaryloxy- (for example, pyridyloxy, isoxazolyloxy, oxazolyloxy, pyrrolyloxy, thienyloxy), in which the heteroaryl is substituted with 0, 1 or 2 R³⁰; in which each R³⁰ is independently selected from halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₈ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl). In certain embodiments, no R³ is substituted on the ring of R¹⁷. In other embodiments, one R³⁰ is substituted on the ring, for example, at a para-position of a phenyl, a meta-position of a phenyl, or at a 3- or 4-position of a heteroaryl or heterocycloalkyl (as counted from the attachment point of the Y⁴, Y⁶ or the ring system denoted by “C”). Certain particular identities of the -G-R¹⁷ moiety will be found by the person of skill in the art in the compounds described below with respect to Table 1. Those of skill in the art will understand that combinations of such -G-R¹⁷ moieties with other subcombinations of features disclosed herein is specifically contemplated.

For example, in certain embodiments of the compounds of formulae (XIV)-(XLI) as described above, the -G-R¹⁷ moiety is selected from

heterocycloalkyl optionally substituted by alkyl and/or halogen, -Q-heteroaryl optionally substituted by unsubstituted (C₁-C₄ alkyl) and/or halogen, H, C(O)tBu and isopropyl, in which each X is independently F, Cl or Br (preferably F or Cl), each R³ is unsubstituted (C₁-C₄ alkyl), unsubstituted (C₁-C₄ haloalkyl) or cycloalkyl optionally substituted with unsubstituted alkyl, unsubstituted (C₁-C₄ alkyl), unsubstituted (C₁-C₄ haloalkyl) or cycloalkyl optionally substituted with unsubstituted alkyl, and each R³⁵ is heterocycloalkyl, optionally substituted with unsubstituted alkyl. In certain such embodiments, Q is a single bond, —CH₂—, —CH₂O—, —OCH₂CH₂—, —CH₂CH₂—, —O—, —CHF—, —CH(CH)—, —C(CH₃)₂—, —CH(OH)—, —CH(COOMe)-, —CH(COOEt)-, —C(O)— or —S(O)₂—. As the person of skill in the art will appreciate, the

moiety and G-R¹⁷ moieties described above can be combined in virtually any combination, and such combinations are specifically contemplated by this disclosure. For example, in certain embodiments of the presently disclosed compounds of structural formulae (XIV)-(XX) as described above, both the

moiety and the -G-R¹⁷ moiety are

(for example, 4-fluorobenzyl or 4-cyanobenzyl). In other embodiments, the

moiety is

(for example, 4-fluorobenzyl or 4-cyanobenzyl), and the -G-R¹⁷ moiety is

(for example, 4-methylphenoxy, 4-methoxyphenoxy, 4-chlorophenoxy, 4-cyanophenoxy, 4-cyano-2-methoxyphenoxy, 3-methylphenoxy, 3-methoxyphenoxy, 3-fluorophenoxy or 3-cyanophenoxy). Of course, the person of skill in the art will recognize that other combinations of

and -G-R¹⁷ can be used. Such combinations of

and -G-R¹⁷ in combination with other combinations of features described herein is specifically contemplated by this disclosure.

In certain embodiments, the presently disclosed compounds have the structural formula (XLII):

in which the variables are independently defined as described above with respect to structural formulae (I)-(XLI). In certain embodiments of the compounds of structural formula (XXI), T is H. In certain embodiments of the compounds of structural formula (XLII), T is

as described above with respect to structural formulae (I)-(XLI), and -G-R¹⁷ is benzoyl, benzenesulfonyl, phenyl, 1-phenylethyl, 1-methyl-1-phenylethyl, —CH(CO(O)(CH₂)₁₋₃H)-phenyl substituted with 0, 1 or 2 R³⁰ as described above, or 4-methoxybenzyl, —C(O)-Cak or —CH₂-Cak. In certain embodiments, G-R¹⁷ is as described above with respect to structural formulae (I)-(XLI), and T is benzoyl, benzenesulfonyl, 1-methyl-1-phenylethyl, heterocycloalkyl, heteroarylmethyl or heteroaryl substituted with 0, 1 or 2 R³⁰ as described above, or 3,5-difluorobenzyl, —C(O)-Cak, (C₁-C₆ alkyl)C(O)— or (C₁-C₈ alkyl). In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (XLIII):

in which the variables are independently defined as described above with respect to structural formulae (I)-(XLII). In certain embodiments of the compounds of structural formula (XLIII), T is H. In certain embodiments of the compounds of structural formula (XLIII), T is

as described above with respect to structural formulae (I)-(XLII), and -G-R¹⁷ is benzoyl, benzenesulfonyl, phenyl, 1-phenylethyl, 1-methyl-1-phenylethyl, —CH(CO(O)(CH₂)₁₋₃H)-phenyl substituted with 0, 1 or 2 R³⁰ as described above, or 4-methoxybenzyl, —C(O)-Cak or —CH₂-Cak. In certain embodiments, G-R¹⁷ is as described above with respect to structural formulae (I)-(XLII), and T is benzoyl, benzenesulfonyl, 1-methyl-1-phenylethyl, heterocycloalkyl, heteroarylmethyl or heteroaryl substituted with 0, 1 or 2 R³⁰ as described above, or 3,5-difluorobenzyl, —C(O)-Cak, (C₁-C₆ alkyl)C(O)— or (C₁-C₆ alkyl). In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (XLIV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, T is (C₁-C₆ alkyl). In other embodiments,

In certain embodiments, the T moiety and the G-R¹⁷ moiety are independently benzyl, 2-phenylethyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (XLV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the Q and the NR¹³ are substituted para from one another on the phenylene. In other embodiments, the Q and the NR¹³ are substituted meta from one another on the phenylene.

In certain embodiments, the presently disclosed compounds have the structural formula (XLVI):

in which the ring system denoted by “C” is heteroarylene (for example, monocyclic heteroarylene), one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment. X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the ring system denoted by “C” is a pyrazolylene (for example, a 1,3-pyrazolylene), a pyridylene (for example, a 2,5-pyridylene). In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (XLVII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenylmethoxy, —C(O)NHCH₂-phenyl, heteroaryl, or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the G and the NR¹ are substituted para with respect to one another on the phenylene. In other embodiments, the G and the NR¹ are substituted meta with respect to one another on the phenylene. In other embodiments, the G and the NR¹ are substituted ortho with respect to one another on the phenylene. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (XLVIII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³; each of the v R¹⁵ can be disposed either spiro-fused ring; and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (XLIX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³; each of the v R¹⁵ can be disposed either spiro-fused ring; and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (L):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment. X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenylmethoxy, —C(O)NHCH₂-phenyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the G and the NR¹ are substituted para with respect to one another on the phenylene. In other embodiments, the G and the NR¹ are substituted meta with respect to one another on the phenylene. In other embodiments, the G and the NR¹ are substituted ortho with respect to one another on the phenylene. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, R³¹ is defined as described above for R³⁰ with respect to the

moiety and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. In certain embodiments, R³¹ is Br. In certain embodiments, the

moiety is benzyl with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the G and the NR¹ are substituted para with respect to one another on the phenylene. In other embodiments, the G and the NR¹ are substituted meta with respect to one another on the phenylene. In other embodiments, the G and the NR¹ are substituted ortho with respect to one another on the phenylene. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenoxy, phenylmethoxy, —C(O)NHCH₂-phenyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the G and the NR¹ are substituted para with respect to one another on the phenylene. In other embodiments, the G and the NR¹ are substituted meta with respect to one another on the phenylene. In other embodiments, the G and the NR¹ are substituted ortho with respect to one another on the phenylene. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LIII):

in which one or two of X¹, X², X³ and X⁴ are N; each of the v R¹⁵ can be disposed either spiro-fused ring; and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LIV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X² and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LV):

in which the ring system denoted by “B” is a heteroarylene, one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the ring system denoted by “B” is a pyrazolylene (for example, a 1,3-pyrazolylene).

In certain embodiments, the presently disclosed compounds have the structural formula (LVI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment. X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LVII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment. X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R¹⁷ as described above. The NR¹ and G-R¹⁷ moieties can, for example, be substituted cis with respect to one another on the cyclohexane ring. In other embodiments, the NR¹ and G-R¹⁷ moieties are substituted trans with respect to one another on the cyclohexane ring. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

certain embodiments, the presently disclosed compounds have the structural formula (LVIII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LIX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, 2-phenylethyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment. X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LXII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. In certain embodiments, the fluorine atom and the —NR¹— are disposed cis with respect to one another on the piperidine. In certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LXIII):

in which R³² is —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄ alkyl), one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³, and the other variables are independently defined as described above with respect to structural formulae (I)-(XIV). In certain embodiments, R³² is H or methyl. In certain embodiments, the fluorine atom and the —NR¹— are disposed cis with respect to one another on the piperidine. In certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R) as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LXIV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the Q and the NR³³ are substituted para from one another on the phenylene. In other embodiments, the Q and the NR¹³ are substituted meta from one another on the phenylene.

In certain embodiments, the presently disclosed compounds have the structural formula (LXV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. In certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LXVI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII), and the G-R¹⁷ moiety is optional. In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the G-R¹⁷ moiety is absent. In certain embodiments, the

moiety and the G-R¹⁷ moiety (if present) are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LXVII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXVIII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the stereogenic center indicated by “*” is racemic. In other embodiments, it is enantiomerically enriched, for example, in the (R)-configuration (i.e., the carbon-NR¹ bond disposed above the plane of the page). In other embodiments, it is enantiomerically enriched, for example, in the (S)-configuration (i.e., the carbon-NR¹ bond disposed below the plane of the page). In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LXVIII):

in which the ring system denoted by “B” is a heteroarylene, one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the ring system denoted by “B” is a triazolylene (for example, a 1,2,3-triazol-1,4-ylene).

In certain embodiments, the presently disclosed compounds have the structural formula (LXIX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment. X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, benzoyl, 1-fluoro-1-phenylmethyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the

moiety is bound at the 4-position of the piperidine. In other embodiments, it is bound at the 3-position of the piperidine. In other embodiments, it is bound at the 2-position of the piperidine.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R⁷ moiety are independently benzyl, benzoyl, 1-fluoro-1-phenylmethyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXIII):

in which one or two of X¹, X², X³ and X⁴ are N and the others are CH or C substituted by one of the w R³; each of the R¹⁵ is substituted on either ring of the 1,2,3,4-tetrahydroisoquinoline; and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXIV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³; each of the R¹⁵ is substituted on either ring of the 1,2,3,4-tetrahydroisoquinoline; and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X^(Z), X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In other embodiments, the Q moiety is —O—CH₂—CH₂—.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXVI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, the NR¹ and the -G-R¹⁷ are disposed cis with respect to one another on the cyclohexane ring. In other embodiments, the NR¹ and the -G-R¹⁷ are disposed trans with respect to one another on the cyclohexane ring. In certain embodiments, Y is N. In other embodiments. Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXVII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXVIII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment. X¹ is N and X^(Z), X and X⁴ are CH or C substituted by one of the w R³. The E moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the

moiety and the E moiety are independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXIX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, E² is —CONR¹— (for example, —CONH—) or —NR¹CO— (for example, —NHCO—), and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment. X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. The -G-R¹⁷ moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). Independently, the

moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the T moiety and the G-R¹⁷ moiety are independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In other embodiments, G is O, CH₂, or SO₂.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXX):

in which two R⁴ on different carbons combine to form a (C₁-C₄ alkylene) bridge, one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment. X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. The E moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). Independently, the T moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LVII). For example, in certain embodiments, the T moiety is independently benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above. In certain embodiments, Y is N. In other embodiments, Y is CH or C substituted by one of the x R⁴. In certain embodiments, the

moiety is

In certain embodiments, the presently disclosed compounds have the structural formula (LXXXI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. In one embodiment, R¹ is H. The —R¹⁷ moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). Independently, the

moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the T moiety is benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above; and the R¹⁷ moiety is phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXXII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment. X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. The E moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). Independently, the T moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the T moiety is benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXXIII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XLIII). In one embodiment. X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. The E moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). The A-(R⁵)_(y) moiety independently be, for example, described reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the T moiety is benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have the structural formula (LXXXIV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH or C substituted by one of the w R³, and all other variables are independently defined as described above with respect to structural formulae (I)-(XXII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one of the w R³. In one embodiment, R¹ is H. The -G-R¹⁷ moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). Independently, the

moiety can be, for example, as described with reference to any of structural formulae (XIII)-(LXXVIII). For example, in certain embodiments, the T moiety is benzyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above; and the R¹⁷ moiety is phenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments of compounds having structural formulae (XIII)-(LXXVIII), the

moiety is p-(trifluoromethyl)phenyl, p-fluorophenoxy, m-chloro-p-cyanophenoxy, p-trifluoromethylphenoxy, m,p-difluorophenoxy, m-cyanophenoxy, p-chlorobenzoyl, 2-(p-fluorophenoxy)ethyl, m-methoxyphenyl, m-fluoro-p-methoxybenzyl, p-methylbenzyl, α,p-difluorobenzyl, p-fluoro-α-hydroxybenzyl, 1-methyl-1-phenylethyl, p-chlorophenyl, p-cyanophenoxy, benzenesulfonyl, tetrahydro-2H-pyran-4-yl, 5-methylisoxazol-3-yl, p-fluorobenzenesulfonyl, p-methoxybenzenesulfonyl, benzyl, p-cyano-o-methoxyphenoxy, p-methoxybenzoyl, p-methoxyphenoxy, benzoyl, p-fluorobenzoyl, cyclohexanecarbonyl, p-methoxybenzoyl, cyclohexylmethyl, pyrid-4-yl, pyrid-4-ylmethyl, phenoxy, phenyl, phenethyl, p-methoxyphenyl, p-fluorophenyl, p-cyanophenyl, p-(trifluoromethyl)benzyl, p-methoxybenzyl, p-fluorobenzyl, m,m-difluorobenzyl p-carbamoylbenzyl, p-(pentafluorosulfanyl)benzyl, p-(pentafluorosulfanyl)phenoxy, p-(cyclopropylsulfonyl)phenoxy, p-(cyclopropylsulfonyl)benzyl, p-(methylsulfonyl)benzyl, p-(methylsulfonyl)phenoxy, p-(trifluoromethylsulfonyl)phenoxy, p-(trifluoromethylsulfonyl)phenyl, p-(methylsulfonyl)phenyl, p-(dimethylcarbamoyl)benzyl, p-(isopropylsulfonyl)phenyl, p-(cyclopropylsulfonyl)phenyl, p-azidobenzoyl, o,p-difluorobenzoyl, o,p-difluorobenzoxy, pyridin-3-yloxy, pyridin-4-yloxy, m,p-difluorobenzoyl, p-fluorobenzyloxy, p-(1-pyrrolidinyl)benzyol, p-(trifluoromethylthio)phenoxy, m-(cyclopropanecarboxamido)phenoxy, p-acetamidophenoxy, m-acetamidophenoxy, p-cyclopropancarboxamidphenoxy, p-morpholinobenzoyl, p-(4-methylpiperzine-1-yl)benzoyl, p-methoxy-o-nitrophenoxy, p-(methylsulfinyl)benzoyl, p-(methylsulfonamido)benzoxy, p-nitrophenoxy, p-aminophenoxy or p-cyanobenzyl.

Another aspect of the disclosure provides compounds of structural formula (LXXXV):

in which each of the variables is independently defined as described above with respect to structural formulae (I)-(LXXXV). For example, in certain embodiments, a compound has structural formula (LXXXVI):

in which each of the variables is independently defined as described above with respect to structural formulae (I)-(LXXVIII).

In certain embodiments of compounds having structural formulae (XIII)-(LXXVI) as described above, the -G-R¹⁷ moiety is p-chlorobenzyl p-fluorobenzyl, p-cyanobenzyl, p-cyano-m-fluorobenzyl, p-cyanobenzoyl, p-cyanobenzenesulfonyl, cyclohexanecarbonyl, benzoyl, benzyl, phenyl, cyclohexylmethyl, phenoxy, phenylmethoxy, 1-phenylethyl, p-nitrophenyl, cyanophenyl, p-(trifluoromethyl)phenyl, p-bromophenyl, 1H-pyrrol-3-yl, 4-morpholinyl, 4-methylpiperazin-1-yl, p-cyanobenzylcarbamoyl, m,m-difluorobenzyl, p-fluoro-m-methylbenzyl, p-methoxybenzyl, p-chlorobenzyl, p-methylbenzoxy, m-fluorophenoxy, p-fluorophenoxy, m-cyanophenoxy, m-methoxyphenoxy, m-methylphenoxy, p-cyanophenoxy, p-fluorophenoxy, pyrid-3-yl, thien-3-yl, phenethyl, α-carboethoxybenzyl, pyrid-4-ylmethyl, 1-(p-cyanophenyl)-1-methylethyl, p-(trifluoromethyl)benzenesulfonyl, p-(trifluoromethyl)phenoxy, p-(trifluoromethyl)benzyl, m-(trifluoromethyl)benzyl, p-methylsulfonylbenxyl, p-methylsulfonylphenoxy, p-acetylphenoxy, p-pyrrolidinylbenzyl, or p-methoxybenzyl,

As the person of skill in the art will recognize, the various embodiments and features described above can be combined to form other embodiments contemplated by the disclosure. For example, in one embodiment of the compounds of certain of structural formulae (I)-(LXXV) as described above, Q is —CH₂—, as described above, and G is —CH₂—, as described above. In another embodiment of the compounds of certain of structural formulae (I)-(LXXV) as described above, x is 0 and each w is 0. In another embodiment of the compounds of certain of structural formulae (I)-(LXXVI), x is 0, each w is 0 and each v is 0.

Moreover, the various -E moieties and T-(“B” ring system)-J- moieties described above with respect to any of structural formulae (I)-(LXXVI) can be combined around the central pyridine, pyrazine, pyridazine or pyrimidine (for example, in any of the ways described with respect to structural formulae (IX)-(XIII)) to form additional embodiments of compounds specifically contemplated by this disclosure.

Examples of compounds according to structural formula (I) include those listed in Table 1. These compounds can be made according to the general schemes described below, for example using procedures analogous to those described below in the Examples.

TABLE 1 No. Name Structure  1 N-(4-(4-cyanobenzyl) piperadin-4-yl)-6-(4- (4-fluorobenzyl)piperizine- 1-carbonyl)picolinamide

 2 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5- (piperazine-1-carbonyl) picolinamide

 3 pyridine-2,5-diylbis((4- (4-fluorobenzyl) piperazin-1-yl) methanone)

 4 N-(1-(4-cyanobenzoyl) piperidin-4-yl)-5-(4- (4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 5 N⁵-(1-(4-cyanobenzyl) piperidin-4-yl)-N⁵-(3- benzylphenyl)pyridine-2,5- dicarboxamide

 6 N-(4-((4-cyanophenyl) sulfonyl)piperidin-4- yl)-5-(4-(4-fluorobenzyl) piperazine-1-carbonyl) picolinamide

 7 N-(1- (cyclohexanecarbonyl) piperidin-4-yl)- 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 8 N-(1- (benzoyl)piperidin-4- yl)-5-(4-(4-fluoro- benzyl)piperazine-1- carbonyl)picolinamide

 9 N-(1-(4-cyanobenzyl)-1H- pyrazol-3-yl)-5- (4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 10 N-(4-benzylphenyl)- 5-(4-(4- fluorobenzyl)piperazine-1- carbonyl)picolinamide

 11 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl- N-(4-phenylphenyl) picolinamide

 12 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl- N-(3-phenylphenyl) picolinamide

 13 N-(1-(cyclohexylmethyl) piperidin-4-yl)-5- (4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 14 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(1-(phenyl) piperidin-4-yl) picolinamide

 15 4-((8-(5-(4- (4-fluorobenzyl) piperazine-1- carbonyl)picolinoyl)-2,8- diazaspiro[4.5]decan-2- yl)methyl)benzonitrile

 16 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(4- phenoxyphenyl) picolinamide

 17 (4-(4-fluorobenzyl) piperazin-1- yl)(6-(4-(benzyloxy) phenyl) pyridin-3-yl) methanone

 18 5-(4-(4-fluorobenzyl) piperazin-1- carbonyl)-N-(1- (1-phenylethyl) piperidin-4-yl) picolinamide

 19 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(2- phenylphenyl) picolinamide

 20 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(4- (4-nitrophenyl) phenyl)picolinamide

 21 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(3- phenoxyphenyl) picolinamide

 22 (6-(3-(benzyloxy)phenyl) pyridin-3-yl)(4-(4- fluorobenzyl)piperazin- 1-yl)methanone

 23 N-(1-(4-cyanobenzyl)-1H- pyrazol-4-yl)-5-(4-(4- fluorobenzyl)piperazine-1- carbonyl)picolinamide

 24 N-(4-(4-cyanophenyl) phenyl)- 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 25 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(4-(4- trifluoromethylphenyl) phenyl)picolinamide

 26 N-(4-benzoylphenyl)-5- (4-(4-fluorobenzyl) piperazine- 1-carbonyl)picolinamide

 27 N-(4-benzyloxyphenyl)- 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 28 N-(4-bromophenyl)-5- (4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 29 N-(4-(4-methoxyphenyl) phenyl)-5-(4-(4- fluorobenzyl)piperazine-1- carbonyl)picolinamide

 30 (6-(4-benzylphenylamino) pyridin-3-yl)(4-(4- fluorobenzyl)piperazin-1- yl)methanone

 31 4-((2-(5-(4-(4-fluorobenzyl) piperazine-1-carbonyl) pyridin-2-yl)-2,8- diazaspiro[4.5] decan-8-yl) methyl)benzonitrile

 32 N-(4-(3-cyanophenyl) phenyl)- 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 33 (6-(3-phenylphenylamino) pyridin-3-yl)(4-(4- fluorobenzyl)piperazin-1- yl)methanone

 34 (4-(4-fluorobenzyl) piperazine- 1-yl)(6-(4- phenoxyphenylamino) pyridin-3-yl)methanone

 35 (6-(4-(4-cyanobenzyl- carbamoyl) phenyl)pyridin-3-yl) (4-(4-fluorobenzyl) pyperazine-1-yl) methanone

 36 (6-(4-(cyanobenzyl) piperidin-4- ylamino)pyridin-3-yl) (4-(4-fluorobenzyl) piperazin- 1-yl)methanone

 37 (6-(4-phenylphenylamino) pyridin-3-yl)(4-(4- fluorobenzyl)piperazin- 1-yl)methanone

 38 N⁵-(1-(4-cyanobenzyl)- 1H-pyrazol-3-yl)-N²- (1-(4-cyanobenzyl) piperidin-4-yl)pyridin- 2,5-dicarboxamide

 39 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl)- N-(4-(1H-pyrrol-3-yl) phenyl)picolinamide

 40 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(4- morpholinophenyl) picolinamide

 41 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl)- N-(4-(4-methylpiperazin-1- yl)phenyl)picolinamide

 42 (6-(3-(4-cyanobenzyl- carbamoyl)phenyl)pyrdin- 3yl)(4-(4-fluorobenzyl) piperazin-1-yl)methanone

 43 N⁵-(1-(4-cyanobenzyl)- 1H-pyrazol-4-yl)-N²- (1-(4- cyanobenzyl)piperidin- 4-yl)pyridine- 2,5-dicarboxamide

 44 (6-(1-(4-fluorobenzyl)- 1H-pyrazol-4-ylamino) pyridin-3-yl)(4-(4- fluorobenzyl)piperazin-1- yl)methanone

 45 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(1- (4-fluorobenzyl)-1H- pyrazol- 4-ylamino)picolinamide

 46 (6-(1-(4-cyanobenzyl) piperidine-4-carboxamido) pyridin-3-yl)(4-(4- fluorobenzyl)piperazin-1- yl)methanone

 47 N-(4-(4-cyanobenzyl- carbamoyl)phenyl)-5- (4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 48 (6-(4-(4-cyanobenzyl- carbamoyl)phenylamino) pyridin-3-yl)(4-(4- fluorobenzyl)piperazin-1- yl)methanone

 49 N-(1-(3,5-difluorobenzyl) piperidin-4-yl)-5- (4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 50 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N- (1-(4-fluoro-3- methylbenzyl)piperidin-4- yl)picolinamide

 51 N-(1-(4-chlorobenzyl) piperidin-4-yl)-5-(4- (4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 52 N-(1-(4-chlorobenzyl) piperidin-4-yl)-5-(4- (4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

 53 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl)- N-(4-(4-methylphenoxy) phenyl)picolinamide

 54 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl)- N-(4-(4-methoxyphenoxy) phenyl)picolinamide

 55 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl)- N-(4-(3-fluorophenoxy) phenyl)picolinamide

 56 N-(4-(3-cyanophenoxy) phenyl)-5-(4-(4- fluorobenzyl) piperazine-1- carbonyl)picolinamide

 57 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(4-(3- methoxyphenoxy) phenyl)picolinamide

 58 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(4- (3-methylphenoxy) phenyl)picolinamide

 59 N-(4-(4-cyanophenoxy) phenyl)-5-(4-(4- fluorobenzyl) piperazine-1- carbonyl)picolinamide

 60 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl)-N- 4-(4-fluorophenoxy) phenyl)picolinamide

 61 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl)- N-(4-pyridine-3-yl) phenyl)picolinamide

 62 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N- (4-(thiophen-3- yl)phenyl)picolinamide

 63 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-(6-(4- cyanophenoxy)pyridin-3- yl)picolinamide

 64 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl)- (6-(3-cyanophenoxy) pyridin-3-yl)picolinamide

 65 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl)- N-(6-(4- fluorophenoxy)pyridin- 3-yl)picolinamide

 66 5-(4-(4-cyano-2-methoxy- phenoxy)piperidine-1- carbonyl)-N- (1-(4-cyanobenzyl) piperidin-4-yl)picolinamide

 67 5-(4-(4-fluoro-4- fluorobenzoyl) piperidine-1-carbonyl)-N- (6-(4-fluorophenoxy) pyridin-3-yl)picolinamide

 68 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4-fluoro-4- fluorobenzoyl)piperidine- 1-carbonyl)picolinamide

 69 5-(4-(4-methoxybenzoyl) piperidine-1-carbonyl)-N- (6-(4-fluorophenoxy) pyridin-3- yl)picolinamide

 70 5-(4-(4-methoxyphenoxy) piperidine-1-carbonyl)-N- (6-(4-fluorophenoxy) pyridin-3-yl)picolinamide

 71 trans-N-(4-(4- cyanophenoxy) cyclohexyl)-5-(4-(4- fluorobenzyl)piperazine-1- carbonyl)picolinamide

 72 5-(4-benzylpiperazine-1- carbonyl)-N-(1- benzylpiperidin- 4-yl)picolinamide

 73 pyridine-2,5-biylbis((4- benzylpiperazin-1- yl)methanone)

 74 6-(4-benzylpiperazine-1- carbonyl)-N-(1- benzylpiperidin- 4-yl)nicotinamide

 75 5,5′-(piperazine-1,4- diylbis(oxomethylene)) bis(N-(1-(4-cyanobenzyl) piperidin-4-yl) picolinamide)

 76 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-5-(4-(4- fluorobenzoyl) piperazine-1- carbonyl) picolinamide

 77 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(4-(4- methoxybenzoyl) piperazine-1- carbonyl)picolinamide

 78 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-5-(4-(4- fluorophenyl- sulfonyl)piperazine-1- carbonyl)picolinamide

 79 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-5-(4-(4- methoxyphenyl- sulfonyl)piperazine-1- carbonyl)picolinamide

 80 5-(4-benzoylpiperazine-1- carbonyl)-N-(1-(4- cyanobenzyl) piperidin-4-yl) picolinamide

 81 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(4- pivaloylpiperazine-1- carbonyl)picolinamide

 82 N-(1-(4-cyanobenzyl) piperidine- 4-yl)-5-(4-(phenylsulfonyl) piperazine-1- carbonyl)picolinamide

 83 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-5-(4-(tetrahydro- 2H- pyran-4-yl)piperazine-1- carbonyl)picolinamide

 84 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-5-(4-isopropyl- piperazine-1- carbonyl)picolinamide

 85 N-(1-benzylpiperidin-4-yl)- 5-(4-((5-methylisoxazol-3- yl)methyl)piperazine-1- carbonyl)picolinamide

 86 N2,N6-bis(1- (4-cyanobenzyl) piperidin-4-yl)pyridine- 2,6-dicarboxamide

 87 N2,N6-bis(1-(4- fluorobenzyl) piperidin-4-yl)pyridine- 2,6-dicarboxamide

 88 (4-(4-fluorobenzyl) piperazin-1- yl)(6-(4-phenethyl- piperazine- 1-carbonyl)pyridin-3-yl) methanone

 89 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-5-(4- (cyclohexanecarbonyl) piperazine-1-carbonyl) picolinamide

 90 (4-phenethylpiperazin-1- yl)(5-(4- phenylpiperazine-1- carbonyl)pyridin-2- yl)methanone

 91 (4-isopropylpiperazin-1- yl)(6-(4- phenethylpiperazine- 1-carbonyl)pyridin-3- yl)methanone

 92 pyridine-2,5-diylbis((4- phenethylpiperazin- 1-yl)methanone)

 93 (4-(4-fluorobenzyl) piperazin- 1-yl)(6-(4- phenethylpiperazine- 1-carbonyl)pyridin-2- yl)methanone

 94 (4-(4-fluorobenzyl) piperazin- 1-yl)(6-(4- phenylpiperazine- 1-carbonyl)pyridin-2- yl)methanone

 95 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(4- (cyclohexylmethyl) piperazine- 1-carbonyl)picolinamide

 96 N-(1-benzylpiperidin-4-yl)- 5-(4-(pyridin-4-yl) piperazine- 1-carbonyl)picolinamide

 97 N-(1-benzylpiperidin- 4-yl)-5-(4- phenylpiperazine- 1-carbonyl)picolinamide

 98 ethyl 2-(4-(5-(4-(4- fluorobenzyl)piperazine- 1-carbonyl)picolinamido) piperidin-1-yl)-2- phenylacetate

 99 N-(4-(4-cyanobenzyl) cyclohexyl)-6-(4-(4- fluorobenzyl)piperazine-1- carbonyl)picolinamide

100 cis-1-(4-cyanobenzyl)-3- fluoropiperidin-4- yl)-5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

101 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(4-(4- methoxybenzyl) piperazine-1- carbonyl)picolinamide

102 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(cis-3- fluoropiperidin- 4-yl)picolinamide

103 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(4- (pyridin-4-ylmethyl) piperazine-1- carbonyl)picolinamide

104 N-(cis-3-fluoro- 1-(pyridin-4- ylmethyl)piperidin- 4-yl)-5- (4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

105 N2-(1-benzylpiperidin- 4-yl)-N5-(biphenyl-4-yl) pyridine-2,5-dicarboxamide

106 N2-(1-benzylpiperidin-4- yl)-N5-(biphenyl-3-yl) pyridine-2,5- dicarboxamide

107 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N- phenylpicolinamide

108 5-(4-benzylphenylamino)- N-(1-(4-cyanobenzyl) piperidin-4-yl) picolinamide

109 5-(biphenyl-4- ylamino)-N-(1-(4- cyanobenzyl)piperidin- 4-yl)picolinamide

110 5-(4-benzylpiperazin-1- yl)-N-(1-(4-cyanobenzyl) piperidin-4-yl) picolinamide

111 N-(1-(2-(4- cyanophenyl)propan- 2-yl)piperidin-4- yl)-5-(4-(4- fluorobenzyl) piperazine-1- carbonyl)picolinamide

112 N-(1-benzylpiperidin-4-yl)- 5-(3-phenoxyphenylamino) picolinamide

113 N-(1-benzylpiperidin-4-yl)- 5-(4-phenoxyphenylamino) picolinamide

114 N-(1-benzylpiperidin-4- yl)-5-(biphenyl-3-ylamino) picolinamide

115 N-benzyl-5-(4-(4- fluorobenzyl) piperazine-1-carbonyl) picolinamide

116 N-benzyl-5-(4-benzyl- piperazine-1- carbonyl)picolinamide

117 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(1-(4- methoxybenzyl) piperidin- 4-yl)picolinamide

118 (R)-N-(1-(4-cyanobenzyl) pyrrolidin-3-yl)-5- (4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

119 N-(1-benzylpiperidin-4- yl)-5-(4′-cyanobiphenyl- 4-ylamino)picolinamide

120 N-(1-benzylpiperidin-4- yl)-5-(4′-methoxybiphenyl- 4-ylamino)picolinamide

121 5-(1-benzyl-1H- 1,2,3-triazol- 4-yl)-N-(1-(4- cyanobenzyl) piperidin-4-yl) picolinamide

122 5-(1-benzyl-1H- 1,2,3-trizol- 4-yl)-N-(1-(4- cyanobenzyl) piperidin-4-yl) picolinamide

123 (S)-N-(1-(4-cyanobenzyl) pyrrolidin-3-yl)-5- (4-(4-fluorobenzyl) piperazine- 1-carbonyl)picolinamide

124 5-(4-benzylpiperidine-1- carbonyl)-N-(1-(4- cyanobenzyl)piperidin-4- yl)picolinamide

125 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- fluorobenzyl)- 3,3-dimethylpiperazine- 1-carbonyl)picolinamide

126 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-5-(1- phenylpiperidin-4- ylamino) picolinamide

127 N-(cis-1-(4- chlorobenzyl)-3- fluoropiperidin- 4-yl)-5-(4-(4- fluorobenzyl)piperazine-1- carbonyl)picolinamide

128 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-5-(4-(4-cyanobenzyl) piperidine-1-carbonyl) picolinamide

129 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) picolinamide

130 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-(4-fluorobenzyl) piperidine-1- carbonyl)picolinamide

131 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-(4-methoxybenzyl) piperidine-1-carbonyl) picolinamide

132 N-(2-(4- cyanobenzyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)- 5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

133 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(2- phenylpropan-2- yl)piperazine-1- carbonyl)picolinamide

134 5-(4-(4-chlorophenyl) piperidine- 1-carbonyl)-N-(1-(4- cyanobenzyl)piperidin-4- yl)picolinamide

135 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-(4-cyanophenoxy) piperidine-1-carbonyl) picolinamide

136 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-(4-fluorobenzoyl) piperidine-1-carbonyl) picolinamide

137 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-5-(3-(4- cyanophenoxy) piperidine-1-carbonyl) picolinamide

138 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-(fluoro(4- fluorophenyl) methyl)piperidine-1- carbonyl)picolinamide

139 5-(1-(4-chlorophenyl) piperidin-4- ylamino)-N-(1-(4- cyanobenzyl) piperidin-4-yl) picolinamide

140 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-(3,5- difluorobenzyl) piperazine-1- carbonyl)picolinamide

141 5-(4-(4- carbamoylbenzyl) piperidine-1- carbonyl)-N- (1-(4-cyanobenzyl) piperidin-4- yl)picolinamide

142 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-((4- fluorophenyl)(hydroxy) methyl)piperidine-1- carbonyl)picolinamide

143 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-(4- methoxyphenoxy) piperidine-1- carbonyl)picolinamide

144 N2-(2-(4- cyanobenzyl)-1,2,3,4- tetrahydroisoquinolin-7- yl)-N5-(4-fluorobenzyl) pyridine-2,5- dicarboxamide

145 N-(1-(4- cyanobenzyl)piperidin-4- yl)-5-(4-(4-methylbenzyl) piperidine-1- carbonyl)picolinamide

146 N-(1-(4- cyanobenzyl)piperidin-4- yl)-5-(4-(3-fluoro-4- methoxybenzyl) piperidine-1- carbonyl)picolinamide

147 N-(1-(4- cyanobenzyl)piperidin-4- yl)-5-(4-(3-methoxybenzyl) piperidine-1- carbonyl)picolinamide

148 N-(1-(4- cyanobenzyl)piperidin-4- yl)-5-(4-(4-fluorophenoxy) piperidine-1- carbonyl)picolinamide

149 N2-(1-(4- cyanobenzyl)piperidin-4- yl)-N5-(2-(4- fluorophenoxy) ethyl)pyridine-2,5- dicarboxamide

150 N-(cis-4-(4-cyanophenoxy) cyclohexyl)-5-(4-(4- fluorobenzyl)piperazine-1- carbonyl)picolinamide

151 N-(trans-4-(4- cyanophenoxy) cyclohexyl)-5-(4-(4- fluorobenzoyl) piperazine-1- carbonyl)picolinamide

152 N-(1-(4- cyanobenzyl)piperidin-4- yl)-5-(3-(4-fluorobenzyl) piperidine-1- carbonyl)picolinamide

153 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(2-(4-fluorobenzyl) piperidine-1- carbonyl)picolinamide

154 5-(4-(4-chlorobenzoyl) piperidine-1-carbonyl)-N- (1-(4- cyanobenzyl)piperidin- 4-yl)picolinamide

155 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(4-(3- cyanophenoxy)piperidine- 1-carbonyl)picolinamide

156 5-(4-(3-chloro-4- cyanophenoxy)piperidine- 1-carbonyl)-N-(1-(4- cyanobenzyl) piperidin-4-yl)picolinamide

157 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(4- (4-(trifluoromethyl) phenoxy) piperidine-1- carbonyl)picolinamide

158 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(4- (3,4-difluorophenoxy) piperidine-1- carbonyl)picolinamide

159 N-(1-(4- cyanobenzyl)piperidin-4- yl)-3-(5,20-dioxo-24- ((3aS,4S,6aR)-2- oxohexahydro- 1H-thieno[3,4-d] imidazol-4- yl)-7,10,13,16- tetraoxa-4,19- diazatetracos-1-ynyl)-5- (4-(4-fluorobenzyl) piperazine-1- carbonyl)picolinamide

160 5-(4-(4- fluorobenzoyl)piperidine- 1-carbonyl)-N-(1-(4- methoxybenzyl)piperidin- 4-yl)picolinamide

161 5-(4-(4- fluorophenoxy)piperidine- 1-carbonyl)-N-(1-(4- methoxybenzyl)piperidin- 4-yl)picolinamide

162 5-(4-(4- cyanophenoxy)piperidine- 1-carbonyl)-N-(1-(4- methoxybenzyl)piperidin- 4-yl)picolinamide

163 5-(4-(4-methoxybenzoyl) piperidine-1-carbonyl)-N- (1-(4-methoxybenzyl) piperidin- 4-yl)picolinamide

164 tert-butyl 3-(2-(1-(4- cyanobenzyl) piperidin-4-ylcarbamoyl)-5- (4-(4-fluorobenzyl) piperazine-1- carbonyl)pyridin-3-yl) prop-2-ynylcarbamate

165 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-5-(4-(4- cyanophenoxy) piperidin-1-yl) picolinamide

166 N2-(1-(4-cyanobenzyl) piperidin-4-yl)-N5-(1-(4- cyanophenyl)piperidin-4- yl)pyridine-2,5- dicarboxamide

167 N-((cis)-4-(4- cyanophenoxy) cyclohexyl)-5-(4-(4- fluorophenoxy)piperidine- 1-carbonyl)picolinamide

168 N-((trans)-4-(4- cyanophenoxy) cyclohexyl)-5-(4-(4- fluorobenzoyl)piperidine- 1-carbonyl)picolinamide

169 N-((trans)-4-(4- cyanophenoxy) cyclohexyl)-5-(4-(4- fluorophenoxy) piperidine-1- carbonyl)picolinamide

170 N-(5-(4-(4-fluorobenzyl) piperazine-1-carbonyl) pyridin-2-yl)biphenyl-4- carboxamide

171 N-((cis)-4-(4- cyanophenoxy) cyclohexyl)-5-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)picolinamide

172 N-((trans)-4-(4- cyanophenoxy) cyclohexyl)-5-(4-(4- methoxyphenoxy) piperidine- 1-carbonyl)picolinamide

173 1-(4-cyanobenzyl)-N-(5-(4- (4-fluorophenoxy) piperidine-1-carbonyl) pyridin-2-yl)piperidine-4- carboxamide

174 N-((cis)-4-(4- cyanophenoxy) cyclohexyl)-5-(4-(4- methoxyphenoxy) piperidine-1- carbonyl)picolinamide

175 1-(4-cyanobenzyl)- N-(5-(4-(4- fluorobenzoyl) piperidine-1- carbonyl)pyridin-2-yl) piperidine- 4-carboxamide

176 N-((cis)-4-(4- cyanophenoxy) cyclohexyl)- 5-((S)-3-(4-fluorophenoxy) pyrrolidine-1-carbonyl) picolinamide

177 N-(5-(4-(4-fluorobenzyl) piperazine-1- carbonyl)pyridin- 2-yl)-6-(4- fluorophenoxy) nicotinamide

178 N-(1-(4- fluorobenzyl)piperidin- 4-yl)-5-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)picolinamide

179 N-(1-(4- fluorobenzyl)piperidin- 4-yl)-5-(4-(4- (trifluoromethyl) phenoxy)piperidine-1- carbonyl)picolinamide

180 N-(1-(4- fluorobenzyl)piperidin- 4-yl)-5-(4-(4- fluorophenoxy) piperidine-1- carbonyl)picolinamide

181 5-(4-(4-fluorobenzoyl) piperidine- 1-carbonyl)-N-(1-(4- fluorobenzyl)piperidin-4- yl)picolinamide

182 (S)-N-(1-(4-fluorobenzyl) piperidin-4-yl)-5-(3-(4- fluorophenoxy) pyrrolidine-1-carbonyl) picolinamide

183 N-(1-(4-fluorobenzyl) piperidin- 4-yl)-5-(4-(4-methoxy- phenoxy)piperidine-1- carbonyl)picolinamide

184 5-(4-(4-methoxybenzoyl) piperidine-1-carbonyl)-N- ((cis)-4-(4- methoxyphenoxy) cyclohexyl)picolinamide

185 N-((cis)-4-(4- methoxyphenoxy) cyclohexyl)-5-(4-(4- (trifluoromethyl)phenoxy) piperidine-1-carbonyl) picolinamide

186 N-((cis)-4-(4- methoxyphenoxy) cyclohexyl)-5-(4-(4- methoxyphenoxy) piperidine-1-carbonyl) picolinamide

187 (4-(4-fluorobenzyl) piperazin-1- yl)(6-(4-(4- (trifluoromethyl) phenoxy)piperidin-1- yl)pyridin-3-yl) methanone

188 4-(1-(5-(4-(4- fluorobenzyl) piperazine-1- carbonyl)pyridin-2- yl)piperidin-4- yloxy)benzonitrile

189 (4-(4-fluorobenzyl) piperazin- 1-yl)(6-(4-(4- methoxybenzoyl) piperidin-1-yl)pyridin-3- yl)methanone

190 N-((cis)-4-(4- cyanophenoxy) cyclohexyl)-5-(4-(4- (trifluoromethyl)phenoxy) piperidine-1-carbonyl) picolinamide

191 5-(4-(4-methoxyphenoxy) piperidine-1-carbonyl)-N- ((cis)-4-(4-(trifluoromethyl) phenoxy) cyclohexyl)picolinamide

192 5-(4-(4-methoxybenzoyl) piperidine-1- carbonyl)-N-((cis)- 4-(4-(trifluoromethyl) phenoxy) cyclohexyl)picolinamide

193 5-(4-(4-cyanophenoxy) piperidine- 1-carbonyl)-N-((cis)-4-(4- (trifluoromethyl)phenoxy) cyclohexyl)picolinamide

194 5-(4-(4-methoxybenzoyl) piperidine-1- carbonyl)-N-(1- (4-(pyrrolidin-1-yl)benzyl) piperidin-4-yl) picolinamide

195 5-(4-(4-methoxyphenoxy) piperidine-1-carbonyl)-N-(1- (4-(pyrrolidin-1-yl)benzyl) piperidin-4-yl) picolinamide

196 5-(4-(4- fluorophenoxy)piperidine- 1-carbonyl)-N- (1-(4-(pyrrolidin- 1-yl)benzyl)piperidin- 4-yl)picolinamide

197 5-(4-(4- cyanophenoxy)piperidine- 1-carbonyl)-N- (1-(4-(pyrrolidin- 1-yl)benzyl) piperidin-4-yl) picolinamide

198 N-((cis)-4-(4-cyano-3- fluorophenoxy)cyclohexyl)- 5-(4-(4-methoxybenzoyl) piperidine-1-carbonyl) picolinamide

199 N-((cis)-4-(4-cyano-3- fluorophenoxy) cyclohexyl)-5-(4-(4- (trifluoromethyl)phenoxy) piperidine-1-carbonyl) picolinamide

200 5-(4-(4-cyanophenoxy) piperidine- 1-carbonyl)-N-(1-(4- fluorobenzyl) piperidin-4-yl)picolinamide

201 N-(1-(4-carbamoylbenzyl) piperidin- 4-yl)-5-(4-(4-fluorobenzyl) piperazine-1-carbonyl) picolinamide

202 N-(1-(4-methoxybenzyl) piperidin-4-yl)-5-(4-(4- (methylsulfonyl)phenoxy) piperidine-1-carbonyl) picolinamide

203 N-(1-(3,5-difluorobenzyl) piperidin-4-yl)-5-(4-(4- (methylsulfonyl)phenoxy) piperidine- 1-carbonyl)picolinamide

204 N-(6-(4- fluorophenoxy)pyridin- 3-yl)-5-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) pyrazine-2-carboxamide

205 N-(6-(4- fluorophenoxy)pyridin- 3-yl)-5-(4-(4- (trifluoromethyl) phenoxy)piperidine- 1-carbonyl) pyrazine-2-carboxamide

206 5-(4-(2,4-difluorobenzoyl) piperidine-1-carbonyl)-N- (6-(4-fluorophenoxy) pyridin-3-yl)pyrazine-2- carboxamide

207 N-(6-(4- fluorophenoxy)pyridin-3- yl)-5-(4-(4- (methylsulfonyl) phenoxy)piperidine-1- carbonyl)pyrazine- 2-carboxamide

208 5-(4-(4- (methylsulfonyl)phenoxy) piperidine-1- carbonyl)-N- (1-(4-(pyrrolidin-1- yl)benzyl) piperidin-4-yl) picolinamide

209 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(3-(4- cyanophenoxy) azetidine-1-carbonyl) picolinamide

210 5-(3-(4- cyanophenoxy)azetidine- 1-carbonyl)-N-(6-(4- fluorophenoxy)pyridin- 3-yl)picolinamide

211 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) pyrazine-2-carboxamide

212 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- (trifluoromethyl) phenoxy)piperidine-1- carbonyl)pyrazine-2- carboxamide

213 6-(4-(2,4-difluorobenzoyl) piperidine-1-carbonyl)- N-(1-(4-(methylsulfonyl) benzyl)piperidin-4- yl)nicotinamide

214 6-(4-(4-cyanophenoxy) piperidine-1-carbonyl)-N- (1-(4-(methylsulfonyl) benzyl)piperidin-4-yl) nicotinamide

215 6-(4-(4-methoxybenzoyl) piperidine-1-carbonyl)-N- (1-(4-(methylsulfonyl) benzyl)piperidin-4- yl)nicotinamide

216 6-(4-(2,4-difluorobenzoyl) piperidine-1-carbonyl)-N- (1-(4-(methylsulfonamido) benzyl)piperidin-4-yl) nicotinamide

217 6-(4-(4- cyanophenoxy)piperidine- 1-carbonyl)-N-(1-(4- (methylsulfonamido)benzyl) piperidin-4-yl)nicotinamide

218 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- (methylsulfonyl) phenoxy)piperidine-1- carbonyl)pyrazine-2- carboxamide

219 N-(1-4-cyanobenzyl) piperidin- 4-yl)-5-(4-(4- (pyrrolidin-1-yl) benzoyl) piperidine-1-carbonyl) pyrazine-2- carboxamide

220 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(4- (4-(4-methylpiperazin-1- yl)benzoyl)piperidine- 1-carbonyl)pyrazine- 2-carboxamide

221 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- (methylsulfonyl) benzoyl)piperidine-1- carbonyl)nicotinamide

222 N-(1-(4- fluorobenzyl)piperidin- 4-yl)-6-(4-(4- (methylsulfonyl) benzoyl)piperidine-1- carbonyl)nicotinamide

223 N-(1-(4- methoxybenzyl)piperidin- 4-yl)-6-(4-(4- (methylsulfonyl) benzoyl)piperidine-1- carbonyl)nicotinamide

224 N-(6-(4-fluorophenoxy) pyridin-3-yl)-6-(4-(4- (methylsulfonyl)benzoyl) piperidine-1- carbonyl)nicotinamide

225 N-(1-(4-fluorobenzyl) piperidin-4-yl)-5-(4-(4- (methylsulfonyl)benzoyl) piperidine-1- carbonyl)picolinamide

226 N-(1-(4- fluorobenzyl)piperidin- 4-yl)-5-(4-(4- (methylsulfonyl) phenoxy)piperidine-1- carbonyl)picolinamide

227 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- (methylsulfonyl) phenoxy)piperidine-1- carbonyl)picolinamide

228 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- (methylsulfonyl) benzoyl)piperidine-1- carbonyl)picolinamide

229 6-(4-(4-(methylsulfonyl) benzoyl)piperidine-1- carbonyl)-N-(1-(4- (pyrrolidin-1-yl)benzyl) piperidin-4-yl) nicotinamide

230 6-(4-(4-(methylsulfonyl) phenoxy) piperidine-1-carbonyl)-N- (1-(4-(pyrrolidin-1-yl) benzyl) piperidin-4-yl) nicotinamide

231 N-(6-(4- fluorophenoxy)pyridin- 3-yl)-5-(4-(4- (methylsulfonyl) phenoxy)piperidine-1- carbonyl)picolinamide

232 N-(6-(4- fluorophenoxy)pyridin- 3-yl)-5-(4-(4- (methylsulfonyl) benzoyl)piperidine-1- carbonyl)picolinamide

233 5-(4-(4-(methylsulfonyl) benzoyl)piperidine-1- carbonyl)-N-(1-(4- (pyrrolidin-1-yl)benzyl) piperidin-4-yl) picolinamide

234 N-(1-(4-methoxybenzyl) piperidin- 4-yl)-5-(4-(4- (methylsulfonyl) benzoyl)piperidine-1- carbonyl)picolinamide

235 N-(6-(4- fluorophenoxy)pyridin- 3-yl)-6-(4-(4- (methylsulfonyl) phenoxy)piperidine-1- carbonyl)nicotinamide

236 N-(1-(3,5- difluorobenzyl) piperidin-4-yl)-6-(4-(4- (methylsulfonyl)phenoxy) piperidine-1-carbonyl) nicotinamide

237 N-(1-(4- methoxybenzyl)piperidin- 4-yl)-6-(4-(4- (methylsulfonyl) phenoxy)piperidine-1- carbonyl)nicotinamide

238 N-(1-(3-methoxybenzyl) piperidin-4-yl)-6-(4-(4- (methylsulfonyl)phenoxy) piperidine-1-carbonyl) nicotinamide

239 6-(4-(4- (methylsulfonyl)phenoxy) piperidine-1- carbonyl)-N-(1-(3- (trifluoromethoxy) benzyl)piperidin-4- yl)nicotinamide

240 6-(4-(4- azidobenzoyl)piperidine- 1-carbonyl)-N-(1-(4- cyanobenzyl)piperidin- 4-yl)nicotinamide

241 N-(1-(3-methoxybenzyl) piperidin-4-yl)-5-(4-(4- (methylsulfonyl)phenoxy) piperidine-1-carbonyl) picolinamide

242 5-(4-(4- (methylsulfonyl)phenoxy) piperidine-1-carbonyl)-N- (1-(3-(trifluoromethoxy) benzyl)piperidin-4-yl) picolinamide

243 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4-(4- methylpiperazin- 1-yl)benzoyl)piperidine-1- carbonyl)nicotinamide

244 6-(4-(4-(4-methylpiperazin- 1-yl)benzoyl)piperidine-1- carbonyl)-N-(1-(4- (trifluoromethoxy)benzyl) piperidin-4-yl)nicotinamide

245 N-(6-(4- fluorophenoxy)pyridin- 3-yl)-6-(4-(4-(4- methylpiperazin- 1-yl)benzoyl)piperidine- 1-carbonyl)nicotinamide

246 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- (cyclopropylsulfonyl) phenoxy)piperidine-1- carbonyl)nicotinamide

247 6-(4-(4- (cyclopropylsulfonyl) phenoxy)piperidine-1- carbonyl)-N-(6-(4- fluorophenoxy)pyridin-3- yl)nicotinamide

248 6-(4-(4- (cyclopropylsulfonyl) phenoxy)piperidine-1- carbonyl)-N- (1-(4-(pyrrolidin- 1-yl)benzyl)piperidin-4- yl)nicotinamide

249 6-(4-(4- (cyclopropylsulfonyl) phenoxy)piperidine-1- carbonyl)- N-(1-(4- (trifluoromethoxy) benzyl)piperidin-4- yl)nicotinamide

250 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- (methylsulfonyl) phenyl)piperazine- 1-carbonyl) picolinamide

251 N-(1-(4-cyanobenzyl) piperidin-4-yl)- 5-(4-(4-(isopropylsulfonyl) phenyl)piperazine- 1-carbonyl) picolinamide

252 N-((trans)-1- (4-cyanobenzyl)-3- fluoropiperidin- 4-yl)-5-(4-(4- (methylsulfonyl)benzoyl) piperidine-1-carbonyl) picolinamide

253 N-((trans)-3-fluoro-1-(4- (trifluoromethoxy)benzyl) piperidin-4-yl)-5-(4-(4- (methylsulfonyl)benzoyl) piperidine-1-carbonyl) picolinamide

254 N-((trans)-1- (4-cyanobenzyl)-3- fluoropiperidin-4-yl)- 5-(4-(4-(methylsulfonyl) phenoxy)piperidine-1- carbonyl)picolinamide

255 N-((trans)-3-fluoro-1-(4- (trifluoromethoxy)benzyl) piperidin-4-yl)-5-(4-(4- (methylsulfonyl)phenoxy) piperidine-1-carbonyl) picolinamide

256 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- (cyclopropylsulfonyl) phenyl)piperazine-1- carbonyl)picolinamide

257 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- (trifluoromethyl- sulfonyl)phenyl)piperazine- 1-carbonyl)picolinamide

258 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(4-(4- (cyclopropanecarbonyl) phenyl)piperazine-1- carbonyl)picolinamide

259 N-(6-(4- acetylphenoxy)pyridin- 3-yl)-5-(4-(4- (methylsulfonyl) phenoxy)piperidine-1- carbonyl)picolinamide

260 N-(1-(4-cyanobenzyl) piperidin-4-yl)-5-(4- (4-(ethylsulfonyl)benzoyl) piperidine-1-carbonyl) picolinamide

261 N-(6-(4- fluorophenylsulfonyl) pyridin-3-yl)-5-(4-(4- (methylsulfonyl)phenoxy) piperidine-1-carbonyl) picolinamide

262 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4-fluorophenyl- sulfonyl)piperidine-1- carbonyl)picolinamide

263 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4-(2,2,2- trifluoroacetyl) phenyl)piperazine-1- carbonyl)picolinamide

264 N2,N5-bis(1- benzylpiperidin- 4-yl)pyridine-2,5- dicarboxyamide

265 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(3-(4- cyanophenoxy) piperidin-1-yl) picolinamide

266 5-(4-(4-chlorobenzoyl) piperidin-1-yl)-N-(1- (4-cyanobenzyl)piperidin- 4-yl)picolinamide

267 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(1-(4- cyanophenyl) piperidin-4-ylamino) picolinamide

268 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(2-(4- fluorophenyl) propan-2-yl) piperazine-1- carbonyl)picolinamide

269 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(pyridin-4-yloxy) piperidine-1-carbonyl) picolinamide

270 (S)-N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(3-(4- fluorophenoxy) pyrrolidine-1-carbonyl) picolinamide

271 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(2,4- difluorobenzoyl) piperidine-1-carbonyl) picolinamide

272 5-(4-(4- fluorobenzoyl)piperidine- 1-carbonyl)-N-(6-(4- fluorophenoxy) pyridin-3-yl)picolinamide

273 5-(4-(4- fluorophenoxy)piperidine- 1-carbonyl)-N-(6-(4- fluorophenoxy) pyridin-3-yl)picolinamide

274 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(3-(4- methoxyphenoxy) piperidine-1-carbonyl) picolinamide

275 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(1-(4- methoxyphenyl) piperidin-4-ylamino) picolinamide

276 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(1-(4- fluorophenyl)piperidin- 4-ylamino)picolinamide

277 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(3-(3- methoxyphenoxy) piperidine-1-carbonyl) picolinamide

278 (R)-N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(3-(4- fluorophenoxy) pyrrolidine-1-carbonyl) picolinamide

279 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-((trans)-4-(4- cyanophenoxy)- 3-fluoropiperidine-1- carbonyl)picolinamide

280 N-(1-(4- cyanobenzyl)piperidine- 4-yl)-5-((1R,3r,5S)-3-(4- cyanophenoxy)-8- azabicyclo[3.2.1]octane-8- carbonyl)picolinamide

281 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(3,4- difluorobenzoyl) piperidine-1-carbonyl) picolinamide

282 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(2,4- difluorophenoxy) piperidine-1-carbonyl) picolinamide

283 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4- (pyridin-3-yloxy) piperidine-1-carbonyl) picolinamide

284 ethyl 4-(1-(6- (1-(4-cyanobenzyl) piperidin-4-ylcarbamoyl) nicotinoyl)piperidin- 4-yloxy) benzoate

285 5-(4-(4- cyanobenzyl)piperazine- 1-carbonyl)-N-(1-(4- methoxybenzyl)piperidin- 4-yl)picolinamide

286 5-(4-(4-cyano-2 methoxyphenoxy) piperidin-1-yl)-N-(1-(4- cyanobenzyl)piperidin-4- yl)picolinamide

287 N-(1-(3,5-difluorobenzyl) piperidin- 4-yl)-5-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) picolinamide

288 N-(1-(3,5-difluorobenzyl) piperidin- 4-yl)-5-(4-(4-fluorobenzoyl) piperidine-1-carbonyl) picolinamide

289 5-(4-(4- cyanophenoxy)piperidine- 1-carbonyl)-N-(1-(3,5- difluorobenzyl)piperidin- 4-yl)picolinamide

290 tert-butyl 3- (2-(1-(4-cyanobenzyl) piperidin-4-ylcarbamoyl)- 5-(4-(4-fluorobenzyl) piperazine-1-carbonyl) pyridin-3-yl) propylcarbamate

291 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-3-(5,21-dioxo-25- ((3aS,4S,6aR)-2- oxohexahydro- 1H-thieno[3,4-d] imidazol-4-yl)- 8,11,14,17- tetraoxa-4,20- diazapentacosyl)- 5-(4-(4- fluorobenzyl)piperazine- 1-carbonyl)picolinamide

292 N-(1-(3,5-difluorobenzyl) piperidin-4-yl)-5-((S)-3-(4- fluorophenoxy)pyrrolidine- 1-carbonyl)picolinamide

293 N-(1-(3,5-difluorobenzyl) piperidin-4-yl)-5-(4-(p- tolyloxy)piperidine-1- carbonyl)picolinamide

294 N-(1-(3,5- difluorobenzyl)piperidin- 4-yl)-5-(4-(4- trifluoromethyl) phenoxy)piperidine-1- carbonyl)picolinamide

295 N-(1-(3,5- difluorobenzyl)piperidin- 4-yl)-5-(4-(4- fluorophenoxy) piperidine-1-carbonyl) picolinamide

296 N-(1-(3,5- difluorobenzyl)piperidin- 4-yl)-5-(4-(4- methoxyphenoxy) piperidine-1-carbonyl) picolinamide

297 N-(1-(3,5-difluorobenzyl) piperidin-4-yl)-5-(4-(3,4- difluorophenoxy) piperidine- 1-carbonyl)picolinamide

298 5-(4-(3,4-difluorobenzoyl) piperidine-1-carbonyl)-N- (1-(3,5-difluorobenzyl) piperidin-4-yl)picolinamide

299 N-((cis)-4-(3,5- difluorophenoxy) cyclohexyl)-5-(4-(4- fluorophenoxy)piperidine- 1-carbonyl)picolinamide

300 N-((cis)-4-(3,5- difluorophenoxy) cyclohexyl)-5-(4-(4- methoxybenzoyl)piperidine- 1-carbonyl)picolinamide

301 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- (trifluoromethyl) phenoxy)piperidin-1- yl)picolinamide

302 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- methoxybenzoyl) piperidin-1-yl) picolinamide

303 5-(4-(4- cyanophenoxy)piperidine- 1-carbonyl)-N-((cis)-4-(4- fluorophenoxy)cyclohexyl) picolinamide

304 5-(4-(4-fluorobenzoyl) piperidine-1-carbonyl)- N-((cis)-4-(4- fluorophenoxy) cyclohexyl)picolinamide

305 N-(2-(4- fluorophenoxy)ethyl)- 5-(4-(4-methoxybenzoyl) piperidine-1-carbonyl) picolinamide

306 5-(4-(4-cyanophenoxy) piperidine- 1-carbonyl)-N-(2-(4- fluorophenoxy) ethyl)picolinamide

307 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(3-(4- fluorobenzyloxy) azetidine-1- carbonyl)picolinamide

308 N-(1-(3,5- difluorobenzyl)piperidin- 4-yl)-5-(3-(4- fluorobenzyloxy) azetidine-1- carbonyl) picolinamide

309 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- methoxybenzoyl) piperidine-1- carbonyl) nicotinamide

310 N-(1-(3,5-difluorobenzyl) piperidin- 4-yl)-6-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) nicotinamide

311 N-((cis)-4-(4- fluorophenoxy) cyclohexyl)-5-(4-(4- methoxybenzoyl)piperidine- 1-carbonyl)picolinamide

312 N-((cis)-4-(4- fluorophenoxy) cyclohexyl)-5-(4-(4- fluorophenoxy)piperidine- 1-carbonyl)picolinamide

313 5-(3-(4-cyanophenoxy) azetidine-1-carbonyl)-N- (1-(3,5- difluorobenzyl)piperidin- 4-yl)picolinamide

314 5-(3- (4-cyanophenyl)-5,6,7,8- tetrahydro- [1,2,4]triazolo[4,3- a]pyrazine-7-carbonyl)-N- (1-(3,5-difluorobenzyl) piperidin-4-yl)picolinamide

315 N-((1s,4s)-4- (4-cyanophenoxy) cyclohexyl)-6-(4-(4- methoxybenzoyl) piperidine- 1-carbonyl)nicotinamide

316 N-((cis)-4-(4- fluorophenoxy) cyclohexyl)- 6-(4-(4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide

317 N-(1-(4- fluorobenzyl)piperidin- 4-yl)-6-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) nicotinamide

318 6-(4-(4-methoxybenzoyl) piperidine- 1-carbonyl)-N-(1-(4- methoxybenzyl) piperidin-4-yl) nicotinamide

319 6-(4-(4- cyanophenoxy)piperidine- 1-carbonyl)-N-(1-(4- methoxybenzyl)piperidin- 4-yl)nicotinamide

320 6-(4-(4- cyanophenoxy)piperidine- 1-carbonyl)-N-(1-(4- fluorobenzyl) piperidin-4-yl) nicotinamide

321 N-((cis)-4-(4- cyanophenoxy) cyclohexyl)-6-(4-(4- cyanophenoxy) piperidine-1-carbonyl) nicotinamide

322 6-(4-(4- cyanophenoxy)piperidine- 1-carbonyl)-N-(1-(3,5- difluorobenzyl)piperidin- 4-yl)nicotinamide

323 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- cyanophenoxy) piperidine-1-carbonyl) nicotinamide

324 6-(4-(4- cyanophenoxy)piperidine- 1-carbonyl)-N-((cis)-4-(4- fluorophenoxy)cyclohexyl) nicotinamide

325 N-(6-(4- fluorophenoxy)pyridin- 3-yl)-6-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) nicotinamide

326 6-(4-(4-cyanophenoxy) piperidine- 1-carbonyl)-N-(6-(4- fluorophenoxy) pyridin-3-yl)nicotinamide

327 6-(4-(4- fluorobenzyl)piperazine- 1-carbonyl)-N-(1-(4- methoxybenzyl) piperidin-4-yl)nicotinamide

328 6-(4-(4-fluorobenzyl) piperizine- 1-carbonyl)-N-(1-(4- fluorobenzyl) piperidin-4-yl) nicotinamide

329 5-(4-(3,4-difluorobenzoyl) piperidine-1- carbonyl)-N-(1- (4-methoxybenzyl) piperidin- 4-yl)picolinamide

330 5-(4-(3,4-difluorobenzoyl) piperidine- 1-carbonyl)-N-(6-(4- fluorophenoxy) pyridin-3-yl)picolinamide

331 5-(4-(2,4-difluorobenzoyl) piperidine- 1-carbonyl)-N-(1-(4- methoxybenzyl) piperidin-4-yl) picolinamide

332 N-((cis)-4-(4- cyanophenoxy) cyclohexyl)-6-(4-(4- fluorobenzyl)piperizine-1- carbonyl)nicotinamide

333 tert-butyl 4-(6-(4-(4- cyanophenoxy) piperidine-1- carbonyl)nicotinamido) piperidine-1-carboxylate

334 6-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(6-(4- fluorophenoxy) pyridin-3-yl)nicotinamide

335 6-(4-(4-cyanophenoxy) piperidine- 1-carbonyl)-N- (piperidin-4-yl) nicotinamide

336 6-(4-(4-cyanophenoxy) piperidine- 1-carbonyl)-N-(1-(4- (pyrrolidin-1- yl)benzyl)piperidin-4- yl)nicotinamide

337 6-(4-(4-cyanophenoxy) piperidine- 1-carbonyl)-N-(1-(4- morpholinobenzyl) piperidin- 4-yl)nicotinamide

338 6-(4-(4-cyanophenoxy) piperidine- 1-carbonyl)-N-(1-(4- (trifluro- methoxy)benzyl)piperidin- 4-yl)nicotinamide

339 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- (trifluoromethyl) phenyl)piperazine-1- carbonyl)picolinamide

340 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4-cyanophenyl) piperazine-1-carbonyl) picolinamide

341 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4-fluorophenyl) piperazine-1-carbonyl) picolinamide

342 5-(4-(2,4-difluorobenzoyl) piperidine- 1-carbonyl)-N-(6-(4- fluorophenoxy) pyridin-3-yl)picolinamide

343 6-(4-(2,4-difluorophenoxy) piperidine- 1-carbonyl)-N-(6-(4- fluorophenoxy) pyridin-3-yl)nicotinamide

344 6-(4-(2,4-difluorophenoxy) piperidine- 1-carbonyl)-N-(1-(4- methoxybenzyl) piperidin-4-yl)nicotinamide

345 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-6-(4-(2,4- difluorophenoxy) piperidine-1-carbonyl) nicotinamide

346 N-(1-(4-cyanobenzyl) piperidin- 4-yl)-6-(4-(2,4- difluorobenzoyl) piperidine-1-carbonyl) nicotinamide

347 6-(4-(2,4-difluorobenzoyl) piperidine- 1-carbonyl)-N-(1-(4- methoxybenzyl) piperidin-4-yl) nicotinamide

348 6-(4-(2,4-difluorobenzoyl) piperidine- 1-carbonyl)-N-(6-(4- fluorophenoxy) pyridin-3-yl)nicotinamide

349 N-((trans)-1-(4- cyanobenzyl)-3- fluoropiperidin- 4-yl)-6-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)nicotinamide

350 N-((trans)-3-fluoro- 1-(4-(trifluoro- methoxy)benzyl) piperidin-4-yl)-6- (4-(4-methoxybenzoyl) piperidine-1- carbonyl)nicotinamide

351 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- cyanophenoxy) piperidin-1-yl)pyridazine- 3-carboxamide

352 N-((trans)-3-fluoro-1-(4- (pyrrolidin- 1-yl)benzyl)piperidin-4- yl)-6-(4-(4- methoxybenzoyl) piperidine- 1-carbonyl)nicotinamide

353 N-((trans)-3-fluoro-1-(4- isopropoxybenzyl) piperidin-4- yl)-6-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) nicotinamide

354 N-((trans)-1-(4-cyano-3- fluorobenzyl)-3- fluoropiperidin- 4-yl)-6-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) nicotinamide

355 6-(4-(4- cyanophenoxy)piperidine- 1-carbonyl)- N-(1-(oxazol-4- ylmethyl)piperidin-4-yl) nicotinamide

356 6-(4-(4- cyanophenoxy)piperidine- 1-carbonyl)-N-(1- (thiazol-2- ylmethyl)piperidin-4-yl) nicotinamide

357 N-(1-(4- cyanobenzyl)piperidin-4- yl)-5-(4-(4- (dimethylcarbamoyl) phenoxy)piperidine-1- carbonyl)picolinamide

358 5-(4-(4- acetylphenoxy)piperidine- 1-carbonyl)-N-(1- (4-cyanobenzyl) piperidin-4-yl) picolinamide

359 5-(4-(4- acetylphenoxy)piperidine- 1-carbonyl)-N- (6-(4-fluorophenoxy) pyridin-3-yl)picolinamide

360 5-(4-(4- (dimethylcarbamoyl) phenoxy)piperidine- 1-carbonyl)- N-(6-(4- fluorophenoxy)pyridin- 3-yl)picolinamide

361 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- (trifluoromethyl) phenoxy) piperidin-1-yl) pyridazine-3- carboxamide

362 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- methoxybenzoyl) piperidin-1-yl) pyridazine- 3-carboxamide

363 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- nitrophenoxy) piperidine-1- carbonyl)nicotinamide

364 6-(4-(4- aminophenoxy)piperidine- 1-carbonyl)-N- (1-(4-cyanobenzyl) piperidin-4-yl) nicotinamide

365 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-5-(4-(4- (pyrrolidin-1-yl) benzoyl) piperidine-1- carbonyl) picolinamide

366 6-(4-(4- acetamidophenoxy) piperidine-1- carbonyl)-N-(1-(4- cyanobenzyl)piperidin-4- yl)nicotinamide

367 N-(1-(4-cyanobenzyl) piperidin-4-yl)- 6-(4-(4- (methylsulfonamido) phenoxy) piperidine-1-carbonyl) nicotinamide

368 N-(6-(4- fluorophenoxy)pyridin- 3-yl)-5-(4-(4- (pyrrolidn-1-yl) benzoyl) piperidine-1-carbonyl) picolinamide

369 5-(4-(4- cyanobenzoyl)piperidine- 1-carbonyl)-N- (1-(4-cyanobenzyl) piperidin-4-yl) picolinamide

370 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- (dimethylamino) phenoxy) piperidine-1- carbonyl) nicotinamide

371 N-(1-(4-cyanobenzyl) piperidin-4- yl)-6-(4-(4-(17-oxo-20- ((3aS,4S,6aR)- 2-oxohexahydro-1H- thieno[3,4-d] imidazol-4-yl)-4,7,10,13- tetraoxa-16- azaicosanamido)phenoxy) piperidine-1-carbonyl) nicotinamide

372 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-(4-(methylthio) benzoyl) piperidine-1-carbonyl) picolinamide

373 6-(4-(4- methoxybenzoyl) piperidine- 1-carbonyl)-N- (1-(4-nitrobenzyl) piperidin-4-yl) nicotinamide

374 1-(4- cyanobenzyl)-4-(5-(4-(4- (methylsulfinyl)benzoyl) piperidine-1- carbonyl)picolinamido) piperidine 1-oxide

375 5-(4-(4-(1H- pyrazol-1-yl)benzoyl) piperidine-1- carbonyl)-N-(1- (4-cyanobenzyl) piperidin-4- yl)picolinamide

376 N-(1-(4- cyanobenzyl) piperidin-4- yl)-5-(4-(4- morpholinobenzoyl) piperidine-1- carbonyl)picolinamide

377 N-(1-(4- cyanobenzyl)piperidin-4- yl)-6-(4-(4- (pyrrolidin-1-yl) benzoyl)piperidine-1- carbonyl)nicotinamide

378 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4-methoxy-2- nitrophenoxy) piperidine-1- carbonyl)nicotinamide

379 N-(6-(4- fluorophenoxy)pyridin- 3-yl)-5-(4-(4- morpholinobenzoyl) piperidine-1- carbonyl)picolinamide

380 N-(1-(4- cyanobenzyl)piperidin-4- yl)-5-(4-(4-(4- methylpiperazin-1- yl)benzoyl) piperidine-1-carbonyl) picolinamide

381 N-(1-(4- fluorobenzyl) piperidin-4- yl)-6-(4-(4- (pyrrolidin-1-yl)benzoyl) piperidine-1- carbonyl)nicotinamide

382 N-(6-(4- fluorophenoxy)pyridin- 3-yl)-6-(4-(4- (pyrrolidin-1-yl)benzoyl) piperidine-1- carbonyl)nicotinamide

383 6-(4-(2-acetamido-4- methoxyphenoxy) piperidine-1-carbonyl)- N-(1-(4-cyanobenzyl) piperidin-4-yl)nicotinamide

384 6-(4-(2-amino-4- methoxyphenoxy) piperidine-1-carbonyl)-N- (1-(4-cyanobenzyl) piperidin-4-yl)nicotinamide

385 N-(1-(4-cyanobenzyl) piperidin-4-yl)-6-(4- (2-(dimethylamino)-4- methoxyphenoxy) piperidine-1-carbonyl) nicotinamide

386 N3,N6-bis(1-(4- cyanobenzyl)piperidin-4- yl)pyridazine-3,6- dicarboxamide

387 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)pyridazine-3- carboxamide

388 N-(1-(4-cyanobenzyl) piperidin-4-yl)-6-(4- (4-cyanophenoxy) piperidine-1- carbonyl)pyridiazine- 3-carboxamide

389 N-(1-(4-cyanobenzyl) piperidin-4-yl)-6-(4- (4-methoxy-2- (methylsulfonamido) phenoxy)piperidine-1 carbonyl)nicotinamide

390 6-(4-(4-acetylphenoxy) piperidine-1- carbonyl)-N-(1-(4- cyanobenzyl) piperidin-4-yl) nicotinamide

391 6-(4-(4-acetylphenoxy) piperidine-1- carbonyl)-N-(1-(4- fluorobenzyl) piperidin-4-yl)nicotinamide

392 6-(4-(4-(1H-pyrazol- 1-yl)benzoyl) piperidine-1- carbonyl)-N-(1-(4- fluorobenzyl)piperidin- 4-yl)nicotinamide

393 6-(4-(4-(1H-pyrazol-1-yl) benzoyl)piperidine- 1-carbonyl)-N-(1-(4- cyanobenzyl)piperidin- 4-yl)nicotinamide

394 N-(1-(4-cyanobenzyl) piperidin-4-yl)-6-(4- (4-methoxy-2-(17-oxo- 21-((3aS,4S,6aR)- 2-oxohexaydro-1H- thieno[3,4-d] imidazol-4-yl)- 4,7,10,13-tetraoxa-16- azahenicosanamido) phenoxy)piperidine- 1-carbonyl)nicotinamide

395 6-(4-(4-acetylphenoxy) piperidine-1- carbonyl)-N-(6-(4- fluorophenoxy) pyridin-3-yl)nicotinamide

396 N-(1-(4-fluorobenzyl) piperidin-4-yl)- 6-(4-(4-(methylsulfonyl) phenoxy) piperidine-1-carbonyl) nicotinamide

397 N-(1-(4-cyanobenzyl) piperidin-4-yl)- 6-(4-(4-(methylsulfonyl) phenoxy) piperidine-1-carbonyl) nicotinamide

398 N-(4-(4-cyanophenoxy) cyclohexyl)- 6-(4-(4-(methylsulfonyl) phenoxy) piperidine-1-carbonyl) nicotinamide

399 N-(1-(4-cyanobenzyl) piperidin-4-yl)- 6-(4-(4-(methylsulfonyl) phenoxy) piperidine-1-carbonyl) pyridazine- 3-carboxamide

400 N-(1-(4-aminobenzyl) piperidin-4- yl)-6-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) nicotinamide

401 N-(1-(4-acetamidobenzyl) piperidin- 4-yl)-6-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) nicotinamide

402 6-(4-(4-acetylphenoxy) piperidine- 1-carbonyl)-N-(4-(4- cyanophenoxy) cyclohexyl)nicotinamide

403 5-(4-(4-methoxybenzoyl) piperidine-1- carbonyl)-N-(1- (4-(14-oxo-18- ((3aS,4S,6aR)-2- oxohexahydro- 1H-thieno[3,4-d] imidazol-4-yl)- 4,7,10-trioxa-13- azaoctadecanamido) benzyl)piperidin-4-yl) picolinamide

404 6-(4-(4- fluorobenzyl)piperazine-1- carbonyl)-N-(1- (4-fluorophenyl) piperidin-4-yl)nicotinamide

405 6-(4-(4- fluorobenzyl)piperazine- 1-carbonyl)-N-(1-(4- methoxyphenyl) piperidin-4-yl)nicotinamide

406 6-(4-(4-acetamidophenoxy) piperidine-1- carbonyl)-N-(1-(4- fluorobenzyl)piperidin-4- yl)nicotinamide

407 6-(4-(4-acetamidophenoxy) piperidine-1- carbonyl)-N-(1-(4- methoxybenzyl) piperidin-4-yl) nicotinamide

408 5-(4-(4-acetamidophenoxy) piperidine-1- carbonyl)-N-(6-(4- fluorophenoxy) pyridin-3- yl)picolinamide

409 N-(1-(4- cyanobenzyl)piperidin-4- yl)-6-(4-(4- (cyclopropanecarboxamido) phenoxy)piperidine- 1-carbonyl) nicotinamide

410 N-(1-(4- cyanobenzyl)piperidin-4- yl)-5-(4-(4- (trifluoromethylthio) phenoxy)piperidine- 1-carbonyl) picolinamide

411 6-(4-(3-acetamidophenoxy) piperidine- 1-carbonyl)-N-(1-(4- cyanobenzyl) piperidin-4-yl)nicotinamide

412 6-(4-(3-acetamidophenoxy) piperidine- 1-carbonyl)-N-(1-(4- methoxybenzyl) piperidin-4-yl) nicotinamide

413 6-(4-(3-acetamidophenoxy) piperidine- 1-carbonyl)-N-(1-(4- fluorobenzyl) piperidin-4-yl) nicotinamide

414 6-(4-(3-acetamidophenoxy) piperidine- 1-carbonyl)-N-(6-(4- fluorophenoxy) pyridin-3-yl) nicotinamide

415 N-(1-(4-cyanobenzyl) piperidin-4-yl)- 5-(4-(4- (trifluoromethylsulfonyl) phenoxy)piperidine-1- carbonyl)picolinamide

416 tert-butyl 3-(5-(1-(4- cyanobenzyl) piperidin-4-ylcarbamoyl)- 2-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)pyridin-3-yl) propylcarbamate

417 N-(1-(4-cyanophenyl) piperidin-4-yl)-6-(4- (4-fluorobenzyl) piperazine-1- carbonyl)nicotinamide

418 6-(4-(4-cyanophenoxy) piperidine-1- carbonyl)-N-(1-(4- cyanophenyl) piperidin-4-yl) nicotinamide

419 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-(thiophene-2- carbonyl) piperidine-1-carbonyl) picolinamide

420 6-(4-(4-cyanophenoxy) piperidine-1- carbonyl)-N-(1-(4- (methylsulfonyl) phenyl)piperidin-4-yl) nicotinamide

421 6-(4-(4-fluorobenzyl) piperazine-1- carbonyl)-N-(1-(4- (methylsulfonyl) phenyl)piperidin-4-yl) nicotinamide

422 6-(4-(4-cyanophenoxy) piperidine-1- carbonyl)-N-(1-(4- fluorophenyl) piperidin-4-yl) nicotinamide

423 6-(4-(4-cyanophenoxy) piperidine-1- carbonyl)-N-(1-(4- methoxyphenyl) piperidin-4-yl) nicotinamide

424 6-(4-(4-methoxybenzoyl) piperidine- 1-carbonyl)-N-(1-(3- (trifluoromethoxy) benzyl)piperidin-4-yl) nicotinamide

425 6-(4-(4-methoxy- benzoyl)piperidine- 1-carbonyl)-N-(1-(3- methoxybenzyl) piperidin-4-yl) nicotinamide

426 N-((3S,4R)-3-fluoro-1-((5- methylisoxazol- 3-yl)methyl) piperidin-4-yl)-6-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)nicotinamide

427 N-((3S,4R)-3-fluoro-1- ((2-methylthiazol- 4-yl)methyl) piperidin-4-yl)-6-(4- (4-methoxybenzoyl) piperidine-1- carbonyl)nicotinamide

428 6-(4-(4-acetamidophenoxy) piperidine- 1-carbonyl)-N-(1-(3- (trifluoromethoxy) benzyl)piperidin-4-yl) nicotinamide

429 6-(4-(3-acetamidophenoxy) piperidine- 1-carbonyl)-N-(1-(3- (trifluoromethoxy) benzyl)piperidin-4-yl) nicotinamide

430 6-(4-(4-methoxybenzoyl) piperidine- 1-carbonyl)-N-(1-(4- (trifluoromethoxy) benzyl)piperidin-4-yl) nicotinamide

431 N-(1-(4-cyanobenzyl) piperidin-4-yl)- 6-(4-(3-(cyclopropane- carboxamido) phenoxy)piperidine-1- carbonyl)nicotinamide

432 6-(4-(3- (cyclopropanecarboxamido) phenoxy)piperidine-1- carbonyl)-N-(1-(4- fluorobenzyl) piperidin-4-yl) nicotinamide

433 6-(4-(3-(cyclopropane- carboxamido) phenoxy)piperidine-1- carbonyl)-N- (6-(4- fluorophenoxy)pyridin- 3-yl)nicotinamide

434 N-((cis)-4-(4- cyanophenoxy)cyclohexyl)- 6-(4-(3- (cyclopropanecarboxamido) phenoxy)piperidine-1- carbonyl)nicotinamide

435 6-(4-(3-(cyclopropane- carboxamido) phenoxy)piperidine-1- carbonyl)-N- (1-(4-methoxybenzyl) piperidin-4-yl)nicotinamide

436 N-(1-(4-cyanobenzyl) piperidin-4-yl)- 6-(4-(4- (trifluoromethylthio) phenoxy)piperidine- 1-carbonyl) pyridazine-3-carboxamide

437 6-(4-(4- acetylphenoxy)piperidine- 1-carbonyl)-N-(1- (4-cyanobenzyl) piperidin-4-yl) pyridazine-3-carboxamide

438 6-(4-(3-(cyclopropane- carboxamido) phenoxy)piperidine-1- carbonyl)- N-(1-(4-(trifluoromethoxy) benzyl)piperidin-4-yl) nicotinamide

439 N-(1-(4-methoxybenzyl) piperidin-4- yl)-6-(4-(4-(pyrrolidin- 1-yl)benzoyl) piperidine-1-carbonyl) nicotinamide

440 6-(4-(4-(pyrrolidin-1-yl) benzoyl)piperidine- 1-carbonyl- N-(1-(4-(trifluoromethoxy) benzyl)piperidin-4- yl)nicotinamide

441 6-(4-(4-(pyrrolidin-1-yl) benzoyl)piperidine- 1-carbonyl)- N-(1-(3-(trifluoromethoxy) benzyl)piperidin-4- yl)nicotinamide

442 N-((cis)-4-(4- cyanophenoxy) cyclohexyl)- 6-(4-(4-(pyrrolidin-1-yl) benzoyl)piperidine-1- carbonyl)nicotinamide

443 N-(1-(3-fluoro-4- methoxybenzyl) piperidin-4-yl)-6-(4-(4- (pyrrolidin-1-yl)benzoyl) piperidine-1-carbonyl) nicotinamide

444 6-(4-(4- (pyrroidin-1-yl)benoyl) piperidine-1- carbonyl)-N-(1-(4- (pyrrolidin-1-yl)benzyl) piperidin-4-yl)nicotinamide

445 6-(4-(4-methoxybenzoyl) piperidine-1- carbonyl)-N-(piperidin- 4-yl)nicotinamide

446 N-(1-(4- isopropoxybenzyl) piperidin- 4-yl)-6-(4-(4- (pyrrolidin-1-yl) benzoyl)piperidine- 1-carbonyl)nicotinamide

447 N-(1-(4-cyano-3- fluorobenzyl) piperidin-4-yl)-6-(4-(4- (pyrrolidin-1-yl)benzoyl) piperidine-1- carbonyl)nicotinamide

448 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- (cyclopropane- sulfonamido) phenoxy)piperidine- 1-carbonyl)nicotinamide

449 6-(4-(4-(cyclopropane- sulfonamido) phenoxy)piperidine-1- carbonyl)-N-(6-(4- fluorophenoxy)pyridin- 3-yl)nicotinamide

450 N-(1-(4-cyanobenzyl) piperidin-4-yl)- 6-(4-(4- (trifluoromethylsulfonyl) phenoxy)piperidine- 1-carbonyl) nicotinamide

451 N-((trans)-1-(4- cyanobenzyl)-3- fluoropiperidin-4- yl)-6-(4-(4- (trifluoromethylsulfonyl) phenoxy)piperidine-1- carbonyl)nicotinamide

452 N-((3R,4R)-1- (4-cyanobenzyl)-3- fluoropiperidin-4- yl)-6-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)nicotinamide

453 N-((3S,4S)-1- (4-cyanobenzyl)-3- fluoropiperidin- 4-yl)-6-(4-(4- methoxybenzoyl)piperidine- 1-carbonyl)nicotinamide

454 N-((cis)-1-(4- cyanobenzyl)-3- fluoropiperidin-4- yl)-6-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)nicotinamide

455 6-(4-(4- (cyclopropanecarbonyl) phenoxy)piperidine-1- carbonyl)-N-(1-(4- (trifluoromethoxy)benzyl) piperidin-4-yl) nicotinamide

456 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- (cyclopropane- carbonyl)phenoxy) piperdine-1-carbonyl) nicotinamide

457 6-(4-(4- (cyclopropanecarbonyl) phenoxy) piperidine-1-carbonyl)- N-(6-(4-fluorophenoxy) pyridin-3-yl)nicotinamide

458 6-(4-(4-(cyclopropane- carbonyl)phenoxy) piperidine-1-carbonyl)- N-(1-(4-methoxybenzyl) piperidin-4-yl) nicotinamide

459 N-(6-(4-cyanophenoxy) pyridin-3-yl)-6-(4- (4-(methylsulfonyl) phenoxy)piperidine-1- carbonyl)nicotinamide

460 N-(6-(4-cyanophenoxy) pyridin-3-yl)-6- (4-(4-methoxybenzoyl) piperidine-1- carbonyl)nicotinamide

461 N-((cis)-3-fluoro-1-(4- (trifluoromethoxy) benzyl)piperidin-4-yl)- 6-(4-(4-methoxybenzoyl) piperidine-1-carbonyl) nicotinamide

462 N-(6-(4-acetylphenoxy) pyridin-3-yl)-6-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)nicotinamide

463 N-(6-(4-cyanophenoxy) pyridin-3-yl)-6-(4- (2,4-difluorobenzoyl) piperidine- 1-carbonyl)nicotinamide

464 N-(6-(4-acetylphenoxy) pyridin-3-yl)-6-(4- (2,4-difluorobenzoyl) piperidine- 1-carbonyl)nicotinamide

465 6-(4-(4-methoxybenzoyl) piperidine-1- carbonyl)-N-(6-(4- (methylsulfonyl) phenoxy)pyridin-3-yl) nicotinamide

466 6-(4-(2,4-difluorobenzoyl) piperidine-1- carbonyl)-N-(6-(4- (methylsulfonyl) phenoxy)pyridin-3-yl) nicotinamide

467 N-(6-(4- fluorophenylsulfonyl) pyridin-3-yl)-6-(4-(4- methoxybenzoyl) piperidine-1-carbonyl) nicotinamide

468 N-(5-(4- cyanophenoxy)pyridin-2- yl)-6-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)nicotinamide

469 N-(5-(4-cyanophenoxy) pyridin-2-yl)-6-(4- (2,4-difluorobenzoyl) piperidine-1- carbonyl)nicotinamide

470 6-(4-(4- fluorophenylsulfonyl) piperidine-1- carbonyl)-N-(1-(4- (trifluoromethoxy) benzyl)piperidin-4-yl) nicotinamide

471 N-(1-(4-cyanobenzyl) piperidin-4-yl)-6-(4- (4-fluorophenylsulfonyl) piperidine-1- carbonyl)nicotinamide

472 N-(6-(4-cyanophenoxy) pyridin-3-yl)-6-(4- (4-fluorophenylsulfonyl) piperidine-1- carbonyl)nicotinamide

473 N-(6-(4-acetylphenoxy) pyridin-3-yl)-6-(4- (4-fluorophenylsulfonyl) piperidine-1- carbonyl)nicotinamide

474 6-(4-(4- fluorophenylsulfonyl) piperidine-1- carbonyl)-N-(1- (4-methoxybenzyl) piperidin-4-yl) nicotinamide

475 6-(4-(4- fluorophenylsulfonyl) piperidine-1- carbonyl)-N-(1-(3- methoxybenzyl) piperidin-4-yl) nicotinamide

476 N-(6-(4-cyanophenoxy) pyridin-3-yl)-6-(4- (4-fluorobenzyl) piperazine-1- carbonyl)nicotinamide

477 N-(6-(4-acetylphenoxy) pyridin-3-yl)-6-(4- (4-fluorobenzyl) piperazine-1- carbonyl)nicotinamide

478 N-(6-(4-cyanophenoxy)-2- methylpyridin-3-yl)-6- (4-(4-methoxybenzoyl) piperidine- 1-carbonyl)nicotinamide

479 N-(6-(4-cyanophenoxy)- 2-methylpyridin- 3-yl)-6-(4-(2,4- difluorobenzoyl) piperidine-1-carbonyl) nicotinamide

480 N-(6-(4- (dimethylcarbamoyl) phenoxy)pyridin-3- yl)-6-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)nicotinamide

481 6-(4-(2,4-difluorobenzoyl) piperidine- 1-carbonyl)-N-(6-(4- (dimethyl- carbamoyl)pheoxy) pyridin-3- yl)nicotinamide

482 N-(1-(4-cyanobenzyl) piperidin-4-yl)-6-(4- (4-methoxybenzoyl) piperidine-1-carbonyl)- N-methylnicotinamide

483 6-(4-(4-methoxybenzoyl) piperidine-1- carbonyl)-N-methyl- N-(1-(4- (trifluoromethoxy) benzyl)piperidin-4- yl)nicotinamide

484 6-(4-(4-methoxybenzoyl) piperidine-1- carbonyl)-N-(1-(4- methoxybenzyl) piperidin-4-yl)- N-methylnicotinamide

485 N-(6-(4-acetylphenoxy) pyridin-3-yl)- 6-(4-(4-(methylsulfonyl) phenoxy)piperidine-1- carbonyl)nicotinamide

486 N-(6-(4-acetylphenoxy) pyiridin-3-yl)-6-(4- (4-(cyclopropylsulfonyl) phenoxy)piperidine-1- carbonyl)nicotinamide

487 N-(6-(4- acetylphenoxy)pyridin-3- yl)-6-(4-(4- (methylsulfonyl) phenyl)piperazine-1- carbonyl)nicotinamide

488 N-(6-(4- acetylphenoxy)pyridin- 3-yl)-6-(4-(4- (dimethylcarbamoyl) phenoxy)piperidine- 1-carbonyl)nicotinamide

489 N-(6-(4- acetylphenoxy)pyridin- 3-yl)-6-(4-(4- (isopropylsulfonyl) phenyl)piperazine-1- carbonyl)nicotinamide

490 N-(1-(4- (dimethylcarbamoyl) benzyl)piperidin- 4-yl)-6-(4-(4- methoxybenzoyl) piperidine-1- carbonyl)nicotinamide

491 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4-fluorobenzyl) piperazin-1-yl)pyridazine- 3-carboxamide

492 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(4-(4- (pentafluorosulfanyl) phenoxy)piperidine- 1-carbonyl)picolinamide

493 N-(1-(4- cyanobenzyl)piperidin- 4-yl)-6-(4-(4- (pentafluorosulfanyl) phenoxy)piperidine- 1-carbonyl)nicotinamide

494 6-(4-(4- (pentafluorosulfanyl) phenoxy)piperidine-1- carbonyl)-N-(1-(4- (trifluoromethoxy) benzyl)piperidin-4- yl)nicotinamide

495 N-(1-(4-methoxybenzyl) piperidin-4-yl)-6-(4-(4- pentafluorosulfanyl) phenoxy)piperidine-1- carbonyl)nicotinamide

496 N-(6-(4-fluorophenoxy) pyridin-3-yl)-6-(4-(4- (pentafluorosulfanyl) phenoxy)piperidine- 1-carbonyl)nicotinamide

497 N-(6-(4-cyanophenoxy) pyridin-3-yl)-6-(4-(4- (pentafluorosulfanyl) phenoxy)piperidine- 1-carbonyl)nicotinamide

498 N-(1-(4-cyanobenzyl)-3,3- difluoropiperidin-4-yl)-6- (4-(4- methoxybenzoyl)piperidine- 1-carbonyl)nicotinamide

For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (for example, alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety can refer to a monovalent radical (for example CH₃—CH₂—), in some circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (for example the C₂ alkylene —CH₂—CH₂— may be described as a C₂ alkyl group), which is equivalent to the term “alkylene.” (Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene). All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S). Nitrogens in the presently disclosed compounds can be hypervalent, for example, an N-oxide or tetrasubstituted ammonium salt. On occasion a moiety may be defined, for example, as (A)_(a)-B—, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B— and when a is 1 the moiety is A-B—.

As used herein, the term “alkyl” includes alkyl, alkenyl and alkynyl groups of a designed number of carbon atoms, desirably from 1 to about 12 carbons (i.e., inclusive of 1 and 12). The term “C_(m)-C_(n) alkyl” means an alkyl group having from m to n carbon atoms (i.e., inclusive of m and n). The term “C_(m)-C_(n) alkyl” means an alkyl group having from m to n carbon atoms. For example, “C₁-C₆ alkyl” is an alkyl group having from one to six carbon atoms. Alkyl and alkyl groups may be straight or branched and depending on context, may be a monovalent radical or a divalent radical (i.e., an alkylene group). In the case of an alkyl or alkyl group having zero carbon atoms (i.e., “Co alkyl”), the group is simply a single covalent bond if it is a divalent radical or is a hydrogen atom if it is a monovalent radical. For example, the moiety “—(C₀-C₆ alkyl)-Ar” signifies connection of an optionally substituted aryl through a single bond or an alkylene bridge having from 1 to 6 carbons. Examples of “alkyl” include, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, 3-hexenyl and propargyl. If the number of carbon atoms is not specified, the subject “alkyl” or “alkyl” moiety has from 1 to 12 carbons.

The term “haloalkyl” is an alkyl group substituted with one or more halogen atoms, for example F, Cl, Br and I. A more specific term, for example, “fluoroalkyl” is an alkyl group substituted with one or more fluorine atoms. Examples of“fluoroalkyl” include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, hexafluoroisopropyl and the like. In certain embodiments of the compounds disclosed herein, each haloalkyl is a fluoroalkyl.

The term “aryl” represents an aromatic carbocyclic ring system having a single ring (for example, phenyl) which is optionally fused to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. “Aryl” includes ring systems having multiple condensed rings and in which at least one is aromatic, (for example, 1,2,3,4-tetrahydronaphthyl, naphthyl). Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl, 2,3-dihydrobenzofuranyl and 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The aryl groups herein are unsubstituted or, when specified as “optionally substituted”, can unless stated otherwise be substituted in one or more substitutable positions with various groups, as described below.

The term “heteroaryl” refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen and sulfur in an aromatic ring. The heteroaryl may be fused to one or more cycloalkyl or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. In certain embodiments, each heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl, pyridinyl-N-oxide, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, and tetrazolyl N-oxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. The heteroaryl groups herein are unsubstituted or, when specified as “optionally substituted”, can unless stated otherwise be substituted in one or more substitutable positions with various groups, as described below.

The term “heterocycloalkyl” refers to a non-aromatic ring or ring system containing at least one heteroatom that is preferably selected from nitrogen, oxygen and sulfur, wherein said heteroatom is in a non-aromatic ring. The heterocycloalkyl may be saturated (i.e., a heterocycloalkyl) or partially unsaturated (i.e., a heterocycloalkenyl). The heterocycloalkyl ring is optionally fused to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/or phenyl rings. In certain embodiments, the heterocycloalkyl groups have from 3 to 7 members in a single ring. In other embodiments, heterocycloalkyl groups have 5 or 6 members in a single ring. Examples of heterocycloalkyl groups include, for example, azabicyclo[2.2.2]octyl (in each case also “quinuclidinyl” or a quinuclidine derivative), azabicyclo[3.2.1]octyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl, piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, 3,4-dihydroisoquinolin-2(1H)-yl, isoindolindionyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide. Especially desirable heterocycloalkyl groups include morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl, tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl, γ-butyrolactonyl (i.e., an oxo-substituted tetrahydrofuranyl), γ-butryolactamyl (i.e., an oxo-substituted pyrrolidine), pyrrolidinyl, piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolindionyl, piperazinonyl. The heterocycloalkyl groups herein are unsubstituted or, when specified as “optionally substituted”, can unless stated otherwise be substituted in one or more substitutable positions with various groups, as described below.

The term “cycloalkyl” refers to a non-aromatic carbocyclic ring or ring system, which may be saturated (i.e., a cycloalkyl) or partially unsaturated (i.e., a cycloalkenyl). The cycloalkyl ring optionally fused to or otherwise attached (for example, bridged systems) to other cycloalkyl rings. Preferred cycloalkyl groups have from 3 to 7 members in a single ring. More preferred cycloalkyl groups have 5 or 6 members in a single ring. Examples of cycloalkyl groups include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl and bicyclo[2.2. I]heptane. The cycloalkyl groups herein are unsubstituted or, when specified as “optionally substituted”, may be substituted in one or more substitutable positions with various groups.

The term “oxa” means a divalent oxygen radical in a chain, sometimes designated as —O—.

The term “oxo” means a doubly bonded oxygen, sometimes designated as ═O or for example in describing a carbonyl “C(O)” may be used to show an oxo substituted carbon.

The term “electron withdrawing group” means a group that withdraws electron density from the structure to which it is attached than would a similarly-attached hydrogen atom. For example, electron withdrawing groups can be selected from the group consisting of halo, cyano, —(C₁-C₄ fluoroalkyl), —O—(C₁-C₄ fluoroalkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), —S(O)₂O—(C₀-C₄ alkyl), —SF₅, NO₂ and —C(O)—Hca in which the Hca includes a nitrogen atom to which the —C(O)— is bound, in which no alkyl, fluoroalkyl or heterocycloalkyl is substituted with an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.

The term “substituted,” when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.

Substituent groups for substituting for hydrogens on saturated carbon atoms in the specified group or radical are, unless otherwise specified, —R⁶⁰, halo, —O⁻M⁺, ═O, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, ═S, —NR⁸⁰R⁸⁰, ═NR⁷⁰, ═N—OR⁷⁰, trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷⁰, —SO₂O⁻M⁺, —SO₂OR⁷⁰, —OSO₂R⁷⁰, —OSO₂O⁻M⁺, —OSO₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —C(O)O⁻M⁺, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)O⁻M⁺, —OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰. Each R⁶⁰ is independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of halo, —O⁻M⁺, ═O, —OR⁷¹, —SR⁷¹, —S⁻M⁺, ═S, —NR⁸¹R⁸¹, ═NR⁷¹, ═N—OR⁷¹, trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷¹, —SO₂O⁻M⁺, —SO₂OR⁷¹, —OSO₂R⁷¹, —OSO₂O⁻M⁺, —OSO₂OR⁷¹, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷¹)O⁻M⁺, —P(O)(OR⁷¹)₂, —C(O)R⁷¹, —C(S)R⁷¹, —C(NR⁷¹)R⁷¹, —C(O)O⁻M⁺, —C(O)OR⁷¹, —C(S)OR⁷¹, —C(O)NR⁸¹R⁸¹, —C(NR⁷¹)NR⁸¹R⁸¹, —OC(O)R⁷¹, —OC(S)R⁷¹, —OC(O)O⁻M⁺, —OC(O)OR⁷¹, —OC(S)OR⁷¹, —NR⁷¹C(O)R⁷¹, —NR⁷¹C(S)R⁷¹, —NR⁷¹CO₂ ⁻M⁺, —NR⁷¹CO₂R⁷¹, —NR⁷¹C(S)OR⁷¹, —NR⁷¹C(O)NR⁸¹R⁸¹, —NR⁷¹C(NR⁷¹)R⁷¹ and —NR⁷¹C(NR⁷¹)NR⁸¹R⁸¹. Each R⁷⁰ is independently hydrogen or R⁶⁰; each R⁸⁰ is independently R⁷⁰ or alternatively, two R⁸⁰'s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have —H or C₁-C₃ alkyl substitution; and each M⁺ is a counter ion with a net single positive charge. Each R⁷¹ is independently hydrogen or R⁶¹, in which R⁶¹ is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of halo, —O⁻M⁺, ═O, —OR⁷², —SR⁷², —S⁻M⁺, ═S, —NR⁸²R⁸², ═NR⁷², ═N—OR⁷², trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷¹, —SO₂O⁻M⁺, —SO₂OR⁷², —OSO₂R⁷², —OSO₂O⁻M⁺, —OSO₂OR⁷², —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷²)O⁻M⁺, —P(O)(OR⁷²)₂, —C(O)R⁷², —C(S)R⁷², —C(NR⁷²)R⁷², —C(O)O⁻M⁺, —C(O)OR⁷², —C(S)OR⁷², —C(O)NR⁸²R⁸², —C(NR⁷²)NR⁸²R⁸², —OC(O)R⁷², —OC(S)R⁷², —OC(O)O⁻M⁺, —OC(O)OR⁷², —OC(S)OR⁷², —NR⁷²C(O)R⁷², —NR⁷²C(S)R⁷², —NR⁷²CO₂ ⁻M⁺, —NR⁷²CO₂R⁷², —NR⁷²C(S)OR⁷², —NR⁷²C(O)NR⁸²R⁸², —NR⁷²C(NR⁷²)R⁷² and —NR⁷²C(NR⁷²)NR⁸²R⁸²; and each R⁸¹ is independently R⁷¹ or alternatively, two R⁸¹s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have —H or C₁-C₃ alkyl substitution. Each R⁷² is independently hydrogen, (C₁-C₆ alkyl) or (C₁-C₆ fluoroalkyl); each R⁸² is independently R⁷² or alternatively, two R⁸²s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include 1, 2, 3 or 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have —H or C₁-C₃ alkyl substitution. Each M⁺ may independently be, for example, an alkali ion, such as K⁺, N⁺, Li⁺; an ammonium ion, such as ⁺N(R⁶⁰)₄; or an alkaline earth ion, such as [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5) (“subscript 0.5 means for example that one of the counter ions for such divalent alkali earth ions can be an ionized form of a presently disclosed compound and the other a typical counter ion such as chloride, or two ionized presently disclosed molecules can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound can serve as the counter ion for such divalent alkali earth ions). As specific examples, —NR⁸⁰R⁸⁰ is meant to include —NH₂, —NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4-methyl-piperazin-1-yl and N-morpholinyl. In certain embodiments, each R⁶ is H or (unsubstituted C₁-C₆ alkyl). In certain embodiments, each R⁷⁰ is H or (unsubstituted C₁-C₆ alkyl). In certain embodiments, each R⁸⁰ is H or (unsubstituted C₁-C₆ alkyl).

Substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, —R⁶⁰, halo, —O⁻M⁻, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰, trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃M⁺, —OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂ ⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previously defined.

Substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and heterocycloalkyl groups are, unless otherwise specified, —R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰, trihalomethyl, —CF₃, —CN, —NO, —NO₂, —S(O)₂R⁷⁰, —S(O)₂—O⁻M⁺, —S(O)₂OR⁷⁰, —OS(O)₂R⁷⁰, —OS(O)₂O⁻M⁺, —OS(O)₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰C(O)OR⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previously defined.

In certain embodiments as described above, the substituent groups on carbon atoms can also or alternatively be —SF₅.

In certain embodiments of the compounds disclosed herein, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

In certain embodiments, an “optionally substituted alkyl,” unless otherwise specified, is substituted with halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl). In certain embodiments. “optionally substituted alkyl” is also or alternatively optionally substituted with —N₃ or —SF₅.

In certain embodiments, an “optionally substituted aryl,” unless otherwise specified, is substituted with halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₈ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³², —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl). In certain embodiments, “optionally substituted aryl” is also or alternatively optionally substituted with —N₃ or —SF₅.

In certain embodiments, an “optionally substituted heteroaryl,” unless otherwise specified, is substituted with halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl). In certain embodiments, “optionally substituted heteroaryl” is also or alternatively optionally substituted with —N₃ or —SF₅.

In certain embodiments, an “optionally substituted cycloalkyl,” unless otherwise specified, is substituted with halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl). In certain embodiments, “optionally substituted cycloalkyl” is also or alternatively optionally substituted with —N₃ or —SF₅.

In certain embodiments, an “optionally substituted heterocycloalkyl,” unless otherwise specified, is substituted with halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted with an (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆ alkyl). In certain embodiments, “optionally substituted heterocycloalkyl” is also or alternatively optionally substituted with —N₃ or —SF₅.

The compounds disclosed herein can also be provided as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salts” or “a pharmaceutically acceptable salt thereof” refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. If the compound is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids. Such salts may be, for example, acid addition salts of at least one of the following acids: benzenesulfonic acid, citric acid, α-glucoheptonic acid, D-gluconic acid, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propanoic acid, succinic acid, sulfuric acid, tartaric acid (d, l, or dl), tosic acid (toluenesulfonic acid), valeric acid, palmitic acid, pamoic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4-chlorobenzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, galactaric acid (mucic acid), D-glucuronic acid, 2-oxo-glutaric acid, glycerophosphoric acid, hippuric acid, isethionic acid (ethanolsulfonic acid), lactobionic acid, maleic acid, 1,5-naphthalene-disulfonic acid, 2-naphthalene-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecyl sulfate, 3-hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid, oleic acid, undecylenic acid, ascorbic acid, (+)-camphoric acid, d-camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid, formic acid, hydriodic acid, hydrobromic acid, hydrochloric acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharine, salicylic acid, gentisic acid, and/or 4-acetamidobenzoic acid.

The compounds described herein can also be provided in prodrug form. “Prodrug” refers to a derivative of an active compound (drug) that requires a transformation under the conditions of use, such as within the body, to release the active drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. Prodrugs are typically obtained by masking a functional group in the drug believed to be in part required for activity with a progroup (defined below) to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active drug. The cleavage of the promoiety can proceed spontaneously, such as by way of a hydrolysis reaction, or it can be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature. The agent can be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it can be supplied exogenously. A wide variety of progroups, as well as the resultant promoieties, suitable for masking functional groups in the active drugs to yield prodrugs are well-known in the art. For example, a hydroxyl functional group can be masked as a sulfonate, ester or carbonate promoiety, which can be hydrolyzed in vivo to provide the hydroxyl group. An amino functional group can be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which can be hydrolyzed in vivo to provide the amino group. A carboxyl group can be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which can be hydrolyzed in vivo to provide the carboxyl group. Other specific examples of suitable progroups and their respective promoieties will be apparent to those of skill in the art.

The compounds disclosed herein can also be provided as N-oxides.

The presently disclosed compounds, salts, prodrugs and N-oxides can be provided, for example, in solvate or hydrate form.

Compounds can be assayed for binding to a membrane-bound adiponectin receptor by performing a competitive binding assay with adiponectin. In one such procedure, HEK 293 cellular membrane is coated onto a COSTAR 384 plate, which is then blocked with 1% casein. Polyhistidine-tagged globular adiponectin and a candidate compound is incubated with the membrane in HEPES buffer. Unbound ligands are washed away and the degree of binding of the adiponectin is determined using horseradish peroxidase-conjugated anti-polyhistidine. Compounds that compete with adiponectin binding to the membrane (i.e., give a reduced signal compared to a control performed without a candidate compound) can be chosen as hits and further screened using the below-described functional assays to identify adiponectin receptor agonists.

An in-cell western assay can be performed to demonstrate the activation of the AMPK pathway in human liver cells by globular adiponectin using glutathione S-transferase (GST). AMPK activity can be measured by the relative concentration of phosphorylated acetyl Co-A carboxylase, which is one of the products of AMPK. An increase in pACC correlates with an increase in the rate of fatty acid oxidation.

The compounds of structural formulae (I)-(LXXXVI) can be administered, for example, orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing one or more pharmaceutically acceptable carriers, diluents or excipients. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (for example, intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.

Pharmaceutical compositions can be made using the presently disclosed compounds. For example, in one embodiment, a pharmaceutical composition includes a pharmaceutically acceptable carrier, diluent or excipient, and compound as described above with reference to structural formulae (I)-(LXXXVI).

In the pharmaceutical compositions disclosed herein, one or more compounds of structural formulae (I)-(LXXXVI) may be present in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and, if desired, other active ingredients. The pharmaceutical compositions containing compounds of structural formulae (I)-(LXXXVI) may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use can be prepared according to any suitable method for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by suitable techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

Formulations for oral use can also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Formulations for oral use can also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethykellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative, flavoring, and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Compounds of structural formulae (I)-(LXXXVI) can be formulated into lotions, oils or powders for application to the skin according to certain methods described below.

Compounds of structural formulae (I)-(LXXXVI) can also be administered in the form of suppositories, for example, for rectal administration of the drug. These compositions can be prepared by mixing the compound with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

Compounds of structural formula (I)-(LXXXVI) can also be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

The compounds disclosed herein can be made using procedures familiar to the person of ordinary skill in the art and as described herein. For example, compounds of structural formula (I) can be prepared according to Schemes 1-6, below, or analogous synthetic schemes:

Referring to Scheme 1, a pyridinedicarboxylic acid monomethyl ester (i), for example, is coupled with an amine (here a substituted 1-benzoylpiperidine-4-amine) to form a carboxymethyl-substituted pyridinecarboxamide (ii). The ester is saponified to form the corresponding carboxylic acid (iii), which is then coupled with a suitable amine (in this case, a substituted 1-benzylpiperazine) to form Compound 4 of Table 1.

Referring to Scheme 2, a bromopyridinedicarboxylic acid, for example, is coupled with an amine (here a substituted 1-benzylpiperidine-4-amine) to form a bromo-substituted pyridinecarboxamide (iv), which is then coupled with a suitable amine (in this case, a substituted 4-phenoxypiperidine) using a palladium catalyst to form Compound 17 of Table 1.

Referring to Scheme 3, a pyridinedicarboxylic acid monomethyl ester (v), for example, is coupled with an amine (here a substituted 1-benzylpiperidine-4-amine) to form a carboxymethyl-substituted pyridinecarboxamide (vi). The ester is saponified to form the corresponding carboxylic acid (vii), which is then coupled with a suitable amine (in this case, a substituted 4-benzoylpiperidine) to form Compound 160 of Table 1.

Referring to Scheme 4, a pyridine dicarboxylic acid (viii), for example, is coupled with one equivalent of an amine (here, a substituted 1-benzylepiperizine), then with methanol and trimethylsilyl(diazomethane) to form a carbomethoxy-substituted pyridinecarboxamide (ix), which is saponified to give a carboxylic acid-substituted pyridinecarboxamide (x). An amine (in this case, 1-phenylpiperazine) is coupled with the carboxylic acid-substituted pyridinecarboxamide (x) to form Compound 94 of Table 1.

Referring to Scheme 5, a bromopyridinecarboxamide (xi) is coupled with a substituted 1-benzylpiperidine-4-carboxamide using a palladium catalyst to form Compound 46 of Table 1. Reactions of this general type are described in more detail, for example, in Wrona, Iwona E. et al., Journal of Organic Chemistry (2010), 75(9), 2820-2835.

Scheme 6 describes a preparation that can be used to make gem-dimethylpiperazines for use in making compounds analogous to Compound 125 of Table 1. A piperazin-2-one is singly protected with trityl chloride, then coupled with an appropriate bromide (here, a substituted benzyl bromide) to form a 4-protected 1-(substituted benzyl)piperazin-2-one. The oxo is convered to a gem-dimethyl using Grignard chemistry, then the trityl is removed to yield the desired gem-dimethyl piperazine. Details are provided in the Examples below, and in Xiao, K-J.; Luo, J-M.; Ye, K-Y.; Wang, Y.; Huang, P-Q. Angew. Chem. Int. Ed. 2010, 49, 3037-3040.

One of skill in the art can adapt the reaction sequences of Schemes 1-6 to fit the desired target molecule. Of course, in certain situations one of skill in the art will use different reagents to affect one or more of the individual steps or to use protected versions of certain of the substituents. Additionally, one skilled in the art would recognize that compounds of structural formulae (I)-(LXXXVI) can be synthesized using different routes altogether.

Compounds suitable for use in the presently disclosed pharmaceutical compositions include compounds of Table 1, above. These compounds can be made according to the general scheme described above, for example using a procedure similar to that described below in the Examples.

While not intending to be bound by theory, the inventors surmise that compounds of structural formulae (I)-(LXXXVI) activate the AMPK pathway. Activation of the AMPK pathway has the effect of increasing glucose uptake, decreasing glycogen synthesis and increasing fatty acid oxidation, thereby reducing glycogen, intracellular triglyceride and fatty acid concentration and causing an increase in insulin sensitivity. Because they activate the AMPK pathway, compounds of structural formulae (I)-(LXXXVI) should also inhibit the inflammatory processes which occur during the early phases of atherosclerosis. Accordingly, compounds of structural formulae (I)-(LXXXVI) can be useful in the treatment of type II diabetes and in the treatment and prevention of atherosclerosis, cardiovascular disease, obesity and non-alcoholic fatty liver disease.

In one aspect and without limitation to theory, the present compounds exert AMPK activating activity by binding to an adiponectin receptor, acting as effective adiponectin mimetics. Adiponectin is a protein hormone exclusively expressed in and secreted from adipose tissue and is the most abundant adipose-specific protein. Adiponectin has been implicated in the modulation of glucose and lipid metabolism in insulin-sensitive tissues. Decreased circulating adiponectin levels have been demonstrated in some insulin-resistant states, such as obesity and type 2 diabetes mellitus and also in patients with coronary artery disease, atherosclerosis and hypertension. Adiponectin levels are positively correlated with insulin sensitivity, HDL (high density lipoprotein) levels and insulin stimulated glucose disposal and inversely correlated with adiposity and glucose, insulin and triglyceride levels. Thiazolidinedione drugs, which enhance insulin sensitivity through activation of the peroxisome proliferator-activated receptor-γ, increase endogenous adiponectin production in humans.

Adiponectin binds its receptors in liver and skeletal muscle and thereby activates the AMPK pathway. Similarly, in one aspect, the present compounds act as adiponectin receptor agonists. Adiponectin receptors 1 and 2 are membrane-bound proteins found in skeletal muscle and liver tissue.

Accordingly, another aspect of the present disclosure relates to a method of activating the AMPK pathway. According to this aspect, a method for activating the AMPK pathway in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In one embodiment, a method of increasing fatty acid oxidation in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI). Acetyl Co-A carboxylase (ACC) catalyzes the formation of malonyl Co-A, a potent inhibitor of fatty acid oxidation; phosphorylation of ACC greatly reduces its catalytic activity, thereby reducing the concentration of malonyl Co-A and increasing the rate of fatty acid oxidation. Because the presently disclosed compounds can increase the rate of phosphorylation of ACC, they can reduce the inhibition of fatty acid oxidation and therefore increase its overall rate.

In another embodiment, a method of decreasing glycogen concentration in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method of increasing glucose uptake in a cell includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method of reducing triglyceride levels in a subject includes administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method of increasing insulin sensitivity of a subject includes administering to the subject an effective amount of a compound, pharmaceutically acceptable salt prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

Accordingly, the compounds and compositions disclosed herein can be used to treat a variety of metabolic disorders. For example, in one embodiment, a method of treating type II diabetes in a subject in need of such treatment includes administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, solvate, hydrate, N-oxide or composition described above. In another embodiment, a method of treating or preventing atherosclerosis or cardiovascular disease in a subject includes administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as compound of one of formulas (I)-(LXXXVI).

As described above, the compounds disclosed herein can act as activators of the AMPK pathway. Accordingly, in another embodiment, a method comprises modulating the AMPK pathway (either in vitro or in vivo) by contacting a cell with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition described above, or administering a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition described above to a mammal (for example, a human) in an amount sufficient to modulate the AMPK activity and study the effects thereby induced. Such methods are useful for studying the AMPK pathway and its role in biological mechanisms and disease states both in vitro and in vivo.

In certain embodiments, the compounds disclosed herein affect lipid signaling pathways. For example, in some embodiments, the compounds up-regulate ceramidase activity. Ceramide is a central player in sphingolipid metabolism, and is the immediate precursor of sphingomyelins and glycosphingolipids as well as the bioactive products sphingosine and sphingosine-1-phosphate. Moreover, endogenous ceramide itself mediates, at least in part, the actions of a variety of stimuli on cell differentiation, apoptosis, and growth suppression. Ceramide is deacylated by ceramidase to form sphingosine, which is in turn phosphorylated to sphingosine-1-phosphate by sphingosine kinase.

Elevated ceramide levels have been shown to induce cell apoptosis, differentiation and senescence. Moreover, elevated ceramide levels are linked to a variety of diseases and disorders, including, for example, Batten's disease, inflammatory bowel diseases, diffuse intravascular coagulation, fever, protein catabolism and/or lipid depletion, hepatosplenomegaly associated with inflammatory or metabolic liver diseases, endomyocarditis, endolithial cell and leucocyte activation, capillary thrombosis, meningo-encephalitis due to infectious agents, complications in organ transplantation, rheumatoid arthritis and connective tissue diseases, autoimmune diseases, hyperthyroidism, damage by radiation/chemotherapy agents and chronic fatigue syndrome.

Up-regulating ceramidase function (and therefore reducing the concentration of ceramide) can be used to treat disorders involving deficient cell proliferation (growth) or in which cell proliferation is otherwise desired, for example, degenerative disorders, growth deficiencies, lesions, physical trauma, and diseases in which ceramide accumulates within cells, such as Fabry disease. Other disorders that may benefit from the activation of ceramidase include neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis and disorders of aging such as immune dysfunction, as well as disorders, such as those listed above, linked to elevated ceramide levels.

The compounds, salts, prodrugs, N-oxides, solvates and hydrates described herein can be administered, for example, to a mammalian host to retard cellular responses associated with the activation of the ceramide-mediated signal transduction pathway. The compounds can be useful, for example, in providing protection against cell senescence or apoptosis, such as occurs as a result of trauma (for example, radiation dermatitis) and aging (for example, of the skin or other organs).

Another embodiment is a method for up-regulating ceramidase function in a cell (either in vivo or in vitro), the method including contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method for decreasing ceramide concentration in a cell (either in vivo or in vitro) includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt prodrug. N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method for inhibiting ceramide-activated responses to stimuli in a cell (either in vivo or in vitro) includes contacting the cell with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition described above. The stimuli can be, for example, stimuli for cell senescence and/or apoptosis.

Another embodiment is a method for treating or preventing a disease or disorder in which cell proliferation is deficient or desired in a subject, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition of such a compound described above, for example, a compound of one of formulas (I)-(LXXXVI). Various applicable diseases and disorders are described above.

Another embodiment is a method for treating a disease or disorder linked to elevated ceramide levels in a subject, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described herein. Various applicable diseases and disorders are described above. In certain embodiments, the subject has a ceramide level higher than about 50 pmol/10⁶ cells.

Moreover, since some drugs can induce high levels of ceramide, the compounds, salts, prodrugs, N-oxides, solvates and hydrates described herein can be usefully co-administered with such drugs in order to at least partially ameliorate this effect. For example, in certain embodiments, an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described herein is co-administered with a corticosteroid (for example, dexamethasone), an anti-inflammatory (for example, indomethacin), an antiviral (for example, interfereon), an immunosuppressant (for example, cyclosporin), a chemotherapy agent (for example, adriamicin), and immunopotentiant (for example, an immunoglobulin or a vaccine), or an andocrinological agent (for example, metimazole). As the person of skill in the art will appreciate, co-administration contemplates not only administration at the same time, but also administration at different times, but with time-overlapping pharmacological effects.

Another embodiment is a method for reducing the effect of aging in the skin of a subject, the method including contacting the skin with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described herein.

Another embodiment is a method for treating or preventing radiation dermatitis in the skin of a subject, the method including contacting the skin with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or composition as described herein.

To identify and select therapeutic compounds for use in treating ceramide-associated conditions, cells (or intracellular components such as microsomes) which have not been exposed to a senescence or apoptosis-inducing agent (for example, cytokines such as TNF-α or exogenous stimuli such as heat, radiation or chemical agents) are exposed to such and agent and to the candidate compound. Inhibition of senescence or apoptosis is measured as a function of cell growth. The person of ordinary skill in the art will be familar with techniques for obtaining such measurements.

For example, inhibition of cell senescence can be measured after serum deprivation in serum-dependent cells. Many cell types are dependent upon serum factors for growth. Thus, deprivation of such cells of serum provides a model for assessment of compounds to modulate cell responses to intracellular ceramide-mediated signal transduction. In particular, withdrawal of serum from serum-dependent cell cultures produces increased intracellular levels of endogenous ceramide and may also increase intracellular levels of endogenous diacyl glycerol (see, e.g., Jayadev, et al., J. Biol. Chem., 270, 2047-2052 (1995)). To evaluate the inhibitory effect of the compounds described herein on ceramide-associated conditions in vitro, the serum withdrawal model can be used. Specifically, 3T3 fibroblast cells can be seeded in 96 well microtiter plates in DMEM in the presence of 10%° fetal bovine serum. The cells are incubated to 90% confluence. The medium is removed, and the cells washed and reincubated in serum-free DMEM. A test compound at a variety of concentrations (for example, 0, 4, 40 or 400 μM) and cell permeable ceramide (for example, 0, 5 or 10 μM) are added to the wells. After 24 hrs. incubation, 0.5 μCi of [³H]thymidine is added to each well for 2 hrs. DNA synthesis in the tested cell population is assessed by conventional techniques for detection of [³H]thymidine incorporation. The results of this assay can be used to establish the cell senescence inhibitory efficacy of the test compound.

Inhibition of cell apoptosis can be determined, for example, using CD95 stimulation. Engagement of cell surface receptor CD95 (also known as Fas/Apo-1 antigen) triggers cell apoptosis. DX2 is a functional anti-FAS (CD95) antibody which will, on binding of CD95, activate the sphingomyelinase catalysis of sphingomyelin hydrolysis and production of ceramide (see, with respect to DX2, Cifone, et al., J. Exp. Med., 177, 1547-1552 (1993)). Thus, binding of CD95 is a model for conduction of apoptosis via the sphingomyelin signal transduction pathway. To assess the inhibitory effect of the compounds disclosed herein on ceramide-mediated cell apoptosis, human T lymphoblasts (Jurkat) are suspended at 2×10⁶ cells/mL in RPMI-1640 supplemented with insulin, transferrin, selenium and glutamine. After incubation for 2 hrs. at room temperature with a test compound, pentoxifylline or a control compound (Ro-1724), 25 ng/mL of anti-FAS antibody is added to each suspension. After another 2 hrs., cell apoptosis is measured as a function of the number of cells (counted by hemocytometer) that excluded the vital dye erythrosin B. The results of the experiment can be used to establish the apoptosis inhibitory efficacy of the test compound.

To assess the inhibitory effect of the compounds disclosed herein on death of human lymphocytes, human peripheral blood lymphocytes are isolated from normal human blood and depleted of monocytes by adherence to a plastic substrate. Lymphocytes are then cultured in RPMI-1640 medium with 10% autologous plasma at an initial concentration of 2×10⁶ cells/mL. Aliquots of the cell samples are divided and one half of the samples are incubated with a test compound or 6,7-dimethoxy-1 (2H)-isoquinoline (Aldrich) for four days. The remaining half of the samples are allowed to rest for four days. Cell viability after four days is determined by erythrosin B dye exclusion in a hemocytometer. The results of the experiment can be used to establish the apoptosis inhibitory efficacy of the test compound on human lymphocytes as compared to untreated lymphocytes.

Ceramide-activated protein kinase (CaPK) is a 97 kDa protein which is exclusively membrane-bound and is believed to serve a role in the sphingomyelin signal transduction pathway. In particular, CaPK is believed to mediate phosphorylation of a peptide derived from the amino acid sequence surrounding Thr.sup.669 of the epidermal growth factor receptor (i.e., amino acids 663-681). This site is also recognized by the mitogen-activated kinase MAP (also known as a family of extracellular signal-regulated kinases). Thus, the effect of the compounds disclosed herein on CaPK activity in cells can be indicative of the effect that the compounds exert on signal transduction in the sphingomyelin pathway. Accordingly, Jurkat cells are suspended at 2×10⁶ cells/mL in RPMI-1640 medium as described above with respect to the cell apoptosis experiment. After incubation for 2 hrs., either a test compound; 20 μM of ceramide or 25 ng/ml of anti-FAS antibody DX2 are added to each suspension and incubated for 15 mins. After centrifugation and washing, the cells were separately homogenized in a dounce homogenizer. Ceramide kinase levels in each test sample can be assayed as described by Liu, et al., J. Biol. Chem., 269, 3047-3052 (1994), which is hereby incorporated by reference herein in its entirety. Briefly, the membrane fraction is isolated from each test sample of treated cell homogenate by ultracentrifugation and run on a 10% PAGE gel. The gel is washed with guanadine-HCl, and renatured in HEPES buffer. Then [³²P]-ATP is added to the gel and left there for 10 mins. Thereafter, the gel is extensively washed with 5% TCA. Autophosphorylated kinase is detected by autoradiography. The results of this assay can be used to establish the CaPK inhibitory efficacy of the compounds disclosed herein.

Ceramidase activity can be measured in a variety of ways. For example, a sample from a subject or a sample of cells can be assayed in vitro for RNA or protein levels, structure, and/or activity of the expressed ceramidase RNA or protein. Many methods standard in the art can be thus employed, including but not limited to ceramidase enzyme assays.

Cellular ceramide levels can be monitored directly, or by indirectly monitoring the concentrations of a ceramide metabolite in a cell. For example, ceramide levels can be directly measured by isolating peripheral blood lymphocytes from a subject. The cells are centrifuged to remove supernatant, and lipids are removed from the cell pellet. The organic phase containing the ceramide can be assayed using the diacylglycerase kinase assay for phosphorylating the ceramide which is then evidenced by autoradiography. Methods for performing diacylglycerase kinase assays are described, for example, in Cifone, M. G. et al., J. Exp. Med., 180(4), 1547-52 (1993), Jayadev et al., J. Biol. Chem., 270, 2047-2052, (1995), and Perry. D. K. et al. Methods Enzymology, 312, 22-31 (2000), each of which is hereby incorporated by reference in its entirety.

The presently disclosed AMPK activating compounds are useful for increasing metabolic efficiency, for example by increasing fiber oxidative capacity, endurance and aerobic workload. In particular, the present compounds are useful for treating and regulating disorders of mitochondrial function, including, without limitation, exercise intolerance, chronic fatigue syndrome, muscle weakness, myoclonus, myoclonus epilepsy, such as associated with ragged-red fibers syndrome, Kearns-Sayre syndrome, Leigh's syndrome, mitochondrial myopathy encephalopathy lactacidosis stroke (MELAS) syndrome and stroke like episodes. The disclosed compounds also are useful for treating muscular dystrophic states, such as Duchenne's and Becker's muscular dystrophies and Friedreich's ataxia.

The presently disclosed AMPK activating compounds also function to reduce oxidative stress and secondary effects of such stress. Many diseases, including several of those listed above, have secondary effects caused by damage due to excessive oxidative stress which can be treated using the compounds disclosed herein. For example, free radical damage has been implicated in neurological disorders, such as Parkinson's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease) and Alzheimers disease. Additional diseases in which excessive free radical damage occurs generally include hypoxic conditions and a variety of other disorders. More specifically, such disorders include ischemia, ischemic reperfusion injury (such as coronary or cerebral reperfusion injury), myocardial ischemia or infarction, cerebrovascular accidents (such as a thromboembolic or hemorrhagic stroke) that can lead to ischemia in the brain, operative ischemia, traumatic hemorrhage (for example, a hypovolemic stroke that can lead to CNS hypoxia or anoxia), resuscitation injury, spinal cord trauma, inflammatory diseases, autoimmune disorders (such as rheumatoid arthritis or systemic lupus erythematosis), Down's syndrome, Hallervorden-Spatz disease, Huntingtons chorea, Wilson's disease, diabetic angiopathy (such as peripheral vascular disease or retinal degeneration), uveitis, chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, asthma, neoplasia, Crohn's disease, inflammatory bowel disease and pancreatitis. Free radical damage is also implicated in a variety of age-related disorders, particularly ophthalmic conditions such as cataracts and age-related macular degeneration.

In particular the present compounds are useful for treating neurological disorders associated with reduced mitochondrial function, oxidative stress, or both. For example, Alzheimer's disease, dementia and Parkinson's disease can be treated using the present AMPK activating compounds.

Metabolic efficiency is enhanced by the disclosed AMPK activating compounds. Thus the compounds can be administered to a subject to improve exercise efficiency and athletic performance. Moreover, conditions including, without limitation, hypoxic states, angina pectoris, coronary ischemia and organ damage secondary to coronary vessel occlusion, intermittent claudication, multi-infarct dementia, myocardial infarction, stroke, high altitude sickness and heart failure, including congestive heart failure can be treated using the disclosed compounds.

Inflammatory disorders and effects can be treated using the present compounds. For example, in one aspect, the present compounds are particularly useful for treating lung inflammation, such as is involved in asthma. COPD and transplant rejection. Similarly, the present compounds are useful in reducing organ inflammation, particularly macrophage-associated inflammation, such as inflammation of the kidney, liver and other organs. The anti-inflammatory activity of the presently disclosed compounds can be assessed as is known to those of skill in the art, for example, by using the mixed lymphocyte response in vitro.

Accordingly, one aspect of the disclosure relates to a method for treating or ameliorating a disorder or condition related to oxidative stress, mitochondrial dysfunction, free radical damage and/or metabolic inefficiency in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.

Another aspect of the present disclosure relates to a method for the treatment or amelioration of a disorder of mitochondrial dysfunction in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. In certain embodiments, the disorder is selected from the group consisting of exercise intolerance, chronic fatigue syndrome, muscle weakness, myoclonus, myoclonus epilepsy (such as associated with ragged-red fibers syndrome), Kearns-Sayre syndrome, Leigh's syndrome, mitochondrial myopathy encephalopathy lactacidosis stroke (MELAS) syndrome and stroke like episodes.

Another aspect of the disclosure relates to a method of increasing metabolic efficiency in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. Such methods can be used to increase fiber oxidative capacity, endurance, aerobic workload, or any combination thereof. These methods can be used, for example, to improve exercise efficiency, exercise endurance and/or athletic performance in a subject.

Another aspect of the present disclosure relates to methods for mimicking the effects of exercise in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.

Another aspect of the disclosure relates to a method for treating or ameliorating a disorder in a subject in need thereof, the disorder being selected from the group consisting of hypoxic states, angina pectoris, coronary ischemia and organ damage secondary to coronary vessel occlusion, intermittent claudication, multi-infarct dementia, myocardial infarction, stroke, high altitude sickness and heart failure, including congestive heart failure, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.

Another aspect of the disclosure relates to a method for the treatment of amelioration of a muscular dystrophic state in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. In certain embodiments, the muscular dystrophic state is Duchenne's muscular dystrophy, Becker's muscular dystrophy, or Freidreich's ataxia.

Another aspect of the disclosure relates to a method for increasing oxidative capacity of a muscle fiber, the method including contacting the muscle fiber with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. The contacting may be performed in vitro or in vivo.

Another aspect of the disclosure relates to a method for reducing oxidative stress in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.

Another aspect of the disclosure relates to a method for reducing free radical damage in a subject in need thereof, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above.

Another aspect of the disclosure relates to a method for treating or ameliorating a disorder or condition in a subject in need thereof, the disorder or condition selected from the group consisting of neurological disorders, hypoxic conditions, ischemia, ischemic reperfusion injury, myocardial ischemia or infarction, cerebrovascular accidents, operative ischemia, traumatic hemorrhage, resuscitation injury, spinal cord trauma, inflammatory diseases, autoimmune disorders. Down's syndrome, Hallervorden-Spatz disease, Huntingtons chorea, Wilson's disease, diabetic angiopathy, uveitis, chronic obstructive pulmonary disease (COPD), asthma, neoplasia, Crohn's disease, inflammatory bowel disease, pancreatitis and age-related disorders, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. Particular examples of such disorders and conditions are discussed above.

Another aspect of the disclosure is a method for treating or ameliorating a neurological disorder in a subject in need thereof, the neurological disorder being associated with reduced mitochondrial function, oxidative stress, or both, the method including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. Particular examples of such neurological disorders are discussed above.

Another aspect of the disclosure relates to a method for reducing oxidative stress in a cell, the method including contacting the cell with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. The contacting may be performed in vitro or in vivo.

Another aspect of the disclosure relates to a method for reducing free radical damage in a cell, the method including contacting the cell with a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. The contacting may be performed in vitro or in vivo.

Another aspect of the disclosure is a method for treating an inflammatory disorder or effect in a subject in need thereof, the method including including administering to the subject an effective amount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceutical composition described above. For example, in one embodiment, the inflammatory disorder or effect is lung inflammation, such as is involved in asthma, COPD and transplant rejection. In another embodiment, the inflammatory disorder or effect is organ inflammation, particularly macrophage-associated inflammation, such as inflammation of the kidney, liver and other organs.

Another embodiment is the use of a compound, pharmaceutically acceptable salt, prodrug. N-oxide (or solvate or hydrate thereof) or composition as described above in the manufacture of a medicament for any of the therapeutic purposes described above. For example, the medicament can be for the reduction of triglyceride levels in a subject, the treatment of type II diabetes in a subject, or the treatment or prevention of atherosclerosis or cardiovascular disease in a subject. In other embodiments, the medicament can be used to reduce the levels of cellular ceramide in a subject, for example in the treatment of Batten's disease.

The compounds disclosed herein can be linked to labeling agents, for example for use in variety of experiments exploring their receptor binding, efficacy and metabolism. Accordingly, another embodiment is a labeled conjugate comprising a compound as disclosed herein covalently linked to a labeling agent, optionally through a linker. Suitable linker and labeling agents will be readily apparent to those of skill in the art upon consideration of the present disclosure. The labeling agent can be, for example, an affinity label such as biotin or strepavidin, a hapten such as digoxigenin, an enzyme such as a peroxidase, or a fluorophoric or chromophoric tag. Any suitable linker can be used. For example, in some embodiments, an ethylene glycol, oligo(ethylene glycol) or poly(ethylene glycol) linker is used. Other examples of linkers include amino acids, which can be used alone or in combination with other linker groups, such as ethylene glycol, oligoethylene glycol or polyethylene glycol. Suitable linkers include, without limitation, single amino acids, as well as di- and tripeptides. In one embodiment, the linker includes a glycine residue. The person of skill in the art will realize, of course, that other linkers and labeling agents can be used. In other embodiments, an alkylene chain is the linker. In other embodiments, the linker has the structure —[(C₀-C₃ alkyl)-Y^(m)-]_(m)—, in which each Y^(m) is —O—, —N(R⁹)—, or L, and m is in the range of 1-40. For example, in certain embodiments, a labeled conjugate has structural formula (LXXXVII):

in which the “LINK” moiety is a linker and is optional, and the “LABEL” moiety is a labeling agent, the LINK)₀₋₁-LABEL moiety is bound to the bracketed compound at any aryl or heteroaryl carbon (for example, of the central pyridine, pyridazine, pyrimidine or pyrazine, of the E moiety (e.g., of an R¹⁷ group thereof as in compound 403), or of the T moiety (e.g., of an “A” ring thereof as in compounds 371 and 394)), and all other variables are as described above, for example with reference to structural formula (I). Any of the compounds disclosed with reference to structural formulae (I)-(LXXXVI) can be used in the labeled conjugate of structural formula (LXXXVII).

For example, in one particular embodiment, a labeled conjugate has structural formula (LXXXVIII):

in which all variables are as described above, for example with reference to any of structural formulae (I)-(LXXXVI). The bond to the bracketed compound can be made, for example, at the central pyridine, pyridazine, pyrimidine or pyrazine.

Another disclosed embodiment of a labeled conjugate has the formula (LXXXIX):

The bond to the bracketed compound can be made, for example, at the central pyridine, pyridazine, pyrimidine or pyrazine.

Compounds of formulae (LXXXIX) can be synthesized by those of skill in the art of organic synthesis, for example by reductive amination of N-Boc-glycine aldehyde with a primary amine H₂NR², to yield R²NHCH₂CH₂NHBoc, which is can be coupled to a pyridinecarboxylic acid to build up the target structure as described herein. The Boc protecting group can be removed, and the resulting amine further elaborated to provide the labeled species.

In another particular embodiment, a labeled conjugate has structural formula (XC):

in which all variables are as described above, for example with reference to any of structural formulae (I)-(LXXXVI). The bond to the bracketed compound can be made, for example, at the central pyridine, pyridazine, pyrimidine or pyrazine. Compound 159 is an example of an embodiment according to structural formula (XC).

Compounds according to structural formula (XC) can be made according to Scheme 7, below, and as described with respect to Examples 159 and 164.

Referring to Scheme 7, a chloropyridinedicarboxylic acid monoethyl ester (xii) is coupled with an amine (here, a substituted 1-benzylpiperazine) to form a carboxymethyl-substituted chloropyridinecarboxamide (xiii), which is coupled with a protected propargyl amine to form a carboxyethyl-substituted alkynylpyridinecarboxamide (xiv). Compound (xiv) is saponified, then coupled with an amine (here, a substituted 1-benzylpiperidine), to form a (3-amino-1-propyne)-substituted pyridinedicarboxamide, Compound 164 of Table 1. Compound 164 is deprotected, and the free amine is coupled with a biotinyl-linked acid to form Compound 159 of Table 1.

The following Examples are intended to further illustrate certain embodiments and are not intended to limit the scope of the disclosure.

EXAMPLES Example 1

The following compounds were made using methods analogous to those of Schemes 1-7; in certain cases, exemplary synthetic procedures are provided.

Compound 1 N-(4-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-fluorobenzyl)piperizine-1-carbonyl)picolinamide

¹H nmr (CD₃OD) δ 8.96 (1H, s), 8.29 (1H, dd, J 8.0, 2.0 Hz), 7.71-7.64 (3H, m), 7.55 (2H, d, J 8.0 Hz), 7.38-7.32 (2H, m), 7.04 (2H, t, J 8.5 Hz), 3.96-3.85 (1H, m), 3.82-3.76 (2H, m), 3.62 (2H, s), 3.54 (2H, s), 3.48-3.43 (2H, m), 2.91 (2H, m), 2.56 (2H, m), 2.45 (2H, m), 2.19 (2H, m), 1.95 (2H, m), 1.74-1.63 (3H, m); m/z: 542 [M+H]⁺.

Compound 2: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(piperazine-1-carbonyl)picolinamide

¹H nmr (CD₃OD) δ 8.67 (1H, s), 8.15 (1H, d, J 8.0 Hz), 7.99 (1H, dd, J 8.0, 2.0), 7.68 (2H, d, J 8.0 Hz), 7.54 (2H, d, J 8.0 Hz), 3.97-3.87 (1H, m), 3.75 (2H, m), 3.62 (2H, s), 3.39 (2H, m), 2.97-2.74 (6H, m), 2.23 (2H, m), 1.96-1.91 (2H, m), 1.80-1.66 (3H, m); m/z: 533 [M+H]⁺.

Compound 3: pyridine-2,5-diylbis((4-(4-fluorobenzyl)piperazin-1-yl)methanone)

¹H nmr (CD₃OD) δ 8.62 (1H, s), 7.97 (1H, dd, J 8.0, 2.0 Hz), 7.66 (1H, d, J 8.0 Hz), 7.38-7.32 (m, 4H), 7.07-7.01 (4H, m), 3.82-3.74 (4H, m), 3.55-3.47 (8H, m), 2.58-2.54 (4H, m), 2.46-2.41 (4H, m); m/z: 520 [M+H]⁺.

Compound 4: N-(1-(4-cyanobenzoyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CD₃OD) δ 8.66 (1H, s), 8.15 (1H, d, J 8.0 Hz), 7.99 (1H, dd, J 8.0, 2.0 Hz), 7.84 (2H, d, J 8.5 Hz), 7.60 (2H, d, J 8.5 Hz), 7.37-7.32 (2H, m), 7.04 (2H, t, J 9.0 Hz), 4.63 (1H, m), 4.24-4.17 (1H, m), 3.79 (2H, m), 3.67-3.52 (4H, m), 3.43 (2H, m), 3.11-3.03 (1H, m), 2.56 (2H, m), 2.43 (2H, m), 2.14-1.85 (2H, m), 1.79-1.62 (2H, m); m/z: 555 [M+H]⁺.

Compound 5: 1N-(1-(4-cyanobenzyl)piperidin-4-yl)-N⁵-(3-benzylphenyl)pyridine-2,5-dicarboxamide

¹H nmr (CDCl₃) δ 9.01 (1H, s), 8.26 (2H, s), 7.96 (1H, d, J 8.0 Hz), 7.87 (1H, s), 7.61 (2H, d, J 8.5 Hz), 7.57 (2H, d, J 8.0 Hz), 7.45 (2H, d, J 8.0 Hz), 7.32-7.16 (m, 7H), 3.99 (3H, s), 3.56 (2H, s), 2.84 (2H, m), 2.22 (2H, m), 2.02 (2H, m), 1.72-1.61 (2H, m); m/z: 530 [M+H]⁺.

Compound 6: N-(4-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.57 (1H, br s), 8.17 (1H, m), 7.91-7.83 (m, 6H), 7.28 (1H, m), 7.01 (2H, m), 3.98-3.77 (5H, m), 3.57-3.30 (4H, m), 2.62-2.31 (6H, m), 2.09 (2H, m), 1.78-1.62 (2H, m); m/z: 591 [M+H]⁺.

Compound 7: N-(1-(cyclohexanecarbonyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

m/z: 537 [M+H]⁺.

Compound 8: N-(1-(benzoyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CD₃OD) δ 8.66 (1H, m), 8.15 (1H, d, J 8.0 Hz), 7.98 (1H, dd, J 8.0, 2.0), 7.48-7.40 (5H, m), 7.37-7.31 (2H, m), 7.07-7.01 (2H, m), 4.62 (1H, m), 4.24-4.14 (1H, m), 3.78 (3H, m), 3.54 (2H, s), 3.43 (2H, m), 3.26-3.00 (3H, m), 2.54 (2H, m), 2.42 (m, 2H), 2.10-1.84 (2H, m), 1.69 (2H, m); m/z: 530 [M+H]⁺.

Compound 9: N-(1-(4-cyanobenzyl)-1H-pyrazol-3-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CD₃OD) δ 8.68 (1H, m), 8.23 (1H, d, J 8.0 Hz), 8.02 (1H, dd, J 8.0, 2.0 Hz), 7.71-7.64 (3H, m), 7.38-7.30 (4H, m), 7.02 (2H, m), 6.80 (1H, m), 5.36 (2H, s), 3.76 (2H, m), 3.52 (2H, s), 3.43 (2H, m), 2.53 (2H, m), 2.41 (2H, m); m/z: 524 [M+H]⁺.

Compound 10: N-(4-benzylphenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 9.88 (1H, s), 8.64 (1H, s), 8.32 (1H, d, J 8.0 Hz), 7.92 (1H, dd, J 8.0, 2.0 Hz), 7.69 (2H, d, J 8.5 Hz), 7.33-7.17 (9H, m), 7.02 (2H, m), 3.98 (2H, s), 3.83 (2H, s), 3.55-3.40 (4H, m), 2.62-2.36 (4H, m); m/z: 510 [M+H]⁺.

Compound 11: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl-N-(4-phenylphenyl)picolinamide

¹H nmr (D₆-DMSO) δ 10.79 (1H, s), 8.73 (1H, m), 8.20 (1H, d, J 8.0 Hz), 8.06 (1H, dd, J 8.0, 2.0), 8.00 (2H, d, J 9.0 Hz), 7.67 (4H, m), 7.44 (2H, t, J 8.0 Hz), 7.35-7.29 (3H, m), 7.13 (2H, t, J 9.0 Hz), 3.66 (2H, m), 3.49 (2H, s), 3.33 (2H, m), 2.44 (2H, m), 2.35 (2H, m); m/z: 495 [M+H]⁺.

Compound 12: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl-N-(3-phenylphenyl)picolinamide

¹H nmr (CDCl₃) δ 9.95 (1H, s), 8.60 (1H, m), 8.28 (1H, d, J 8.0 Hz), 7.96 (1H, m), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.70 (1H, m), 7.57 (2H, d, J 7.0 Hz), 7.42-7.19 (7H, m), 6.95 (2H, m), 3.76 (2H, m), 3.46 (2H, s), 3.37 (2H, m), 2.49 (2H, m), 2.36 (2H, m); m/z: 495 [M+H]⁺.

Compound 13: N-(1-(cyclohexylmethyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.56 (1H, s), 8.18 (1H, d, J 8.0 Hz), 7.98 (1H, d, J 8.0 Hz), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.29-7.24 (2H, m), 7.03-6.95 (2H, m), 4.07 (1H, m), 3.79 (2H, m), 3.50 (2H, s), 3.38 (2H, m), 3.20-3.10 (2H, m), 2.97 (1H, d, J 5.0 Hz), 2.60-2.35 (8H, m), 2.16-2.06 (2H, m), 1.95-1.60 (6H, m), 1.31-1.08 (4H, m), 1.01-0.86 (2H, m); m/z: 522 [M+H]⁺.

Compound 14: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(phenyl)piperidin-4-yl)picolinamide

¹H nmr (D₆-DMSO) δ 8.73 (1H, d, J 9.0 Hz), 8.62 (1H, m), 8.06 (1H, d, J 8.0 Hz), 7.98 (1H, dd, J 8.0, 2.0 Hz), 7.35-7.28 (2H, m), 7.21-7.08 (4H, m), 6.96-6.91 (2H, m), 6.73 (1H, m), 3.97 (1H, m), 3.72-3.58 (4H, m), 3.47 (2H, s), 2.82-2.70 (2H, m), 2.41 (2H, m), 2.31 (2H, m), 1.88-1.74 (4H, m); m/z: 503 [M+H]⁺.

Compound 15: 4-((8-(5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinoyl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)benzonitrile

¹H nmr (D₆-DMSO) δ 8.56 (1H, s), 7.91 (2H, d, J 8.5 Hz), 7.78 (2H, m), 7.57 (1H, t, J 8.0 Hz), 7.49 (1H, m), 7.32 (2H, m), 7.13 (2H, m), 3.62 (4H, m), 3.47 (4H, m), 3.40-3.20 (8H, m), 2.44-2.37 (6H, m), 1.58 (4H, m); m/z: 582 [M+H]⁺.

Compound 16: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-phenoxyphenyl)picolinamide

¹H nmr (CDCl₃) δ 9.84 (1H, s), 8.58 (1H, m), 8.26 (1H, d, J 8.0 Hz), 7.85 (1H, dd, J 8.0, 2.0), 7.67 (2H, d, J 9.0 Hz), 7.30-7.18 (4H, m), 7.06-6.90 (7H, m), 3.76 (2H, m), 3.46 (2H, s), 3.37 (2H, m), 2.49 (2H, m), 2.35 (2H, m); m/z: 512 [M+H]⁺.

Compound 17: (4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-(benzyloxy)phenyl)pyridin-3-yl)methanone

To a mixture of (4-(4-fluorobenzyl)piperazin-1-yl)(6-bromopyridin-3-yl)methanone (0.048 g, 0.13 mmol, 1.0 eq), 4-benzyloxyphenylboronic acid (0.040 g, 0.18 mmol, 1.4 eq), potassium phosphate (0.053 g, 0.25 mmol, 1.9 eq), S-Phos (0.006 g, 0.01 mmol, 0.1 eq), and tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.01 mmol, 0.01 eq) was added 1-butanol-water (1.25 mL, 4:1). Following a 5 minute purge of the reaction mixture with argon, the reaction vessel was scaled and heated at 100° C. for 10 hours. The reaction mixture was filtered through Celite®, eluting with 5% MeOH—CH₂Cl₂ and purified by RP-HPLC to provide Compound 17. ¹H nmr (D₆-DMSO) δ 8.61 (1H, s), 8.06 (2H, d, J 9.0 Hz), 7.95 (1H, d, J 8.0 Hz), 7.83 (1H, dd, J 8.0, 2.0 Hz), 7.48-7.30 (7H, m), 7.16-7.10 (4H, m), 5.16 (2H, s), 3.61 (2H, m), 3.48 (2H, s), 3.37 (2H, m), 2.38 (4H, m); m/z: 483 [M+H]⁺.

Compound 18: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(1-phenylethyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.50 (1H, s), 8.13 (1H, d, J 8.0 Hz), 7.88 (1H, d, J 8.0 Hz), 7.78 (1H, dd, J 8.0, 2.0 Hz), 7.32-7.18 (7H, m), 6.94 (2H, m), 3.98-3.86 (1H, m), 3.74 (2H, m), 3.44 (2H, s), 3.32 (2H, m), 3.14 (1H, m), 2.98-2.85 (1H, m), 2.47 (2H, m), 2.38-2.14 (4H, m), 1.98 (2H, m), 1.86-1.62 (3H, m), 1.48 (4H, m); m/z: 531 [M+H]⁺.

Compound 19: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(2-phenylphenyl)picolinamide

¹H nmr (CDCl₃) δ 10.15 (1H, s), 8.56 (1H, d, J 8.0 Hz), 8.35 (1H, m), 8.22 (1H, d, J 8.0 Hz), 7.78 (1H, dd, J 8.0, 2.0 Hz), 7.46-7.34 (6H, m), 7.29-7.13 (4H, m), 6.95 (2H, m), 3.73 (2H, m), 3.53-3.22 (4H, m), 2.47 (2H, m), 2.32 (2H, m); m/z: 496 [M+H]⁺.

Compound 20: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-nitrophenyl)phenyl) picolinamide

¹H nmr (D₆-DMSO) δ 10.93 (1H, s), 8.74 (1H, m), 8.28 (2H, d, J 9.0 Hz), 8.20 (1H, d, J 8.0 Hz), 8.11-8.05 (3H, m), 7.97 (2H, d, J 9.0 Hz), 7.82 (2H, d, J 9.0 Hz), 7.35-7.30 (2H, m), 3.65 (2H, m), 3.49 (2H, s), 3.35 (2H, m), 2.43 (2H, m), 2.35 (2H, m); m/z: 541 [M+H]⁺.

Compound 21: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(3-phenoxyphenyl)picolinamide

¹H nmr (CDCl₃) δ 9.85 (1H, s), 8.56 (1H, m), 8.24 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 8.0, 2.0 Hz), 7.47-7.40 (2H, m), 7.32-7.18 (5H, m), 7.00-6.91 (SH, m), 6.77-6.71 (1H, m), 3.76 (2H, m), 3.46 (2H, s), 3.36 (2H, m), 2.49 (2H, m), 2.36 (2H, m); m/z: 512 [M+H]⁺.

Compound 22: (6-(3-(benzyloxy)phenyl)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

¹H nmr (CDCl₃) δ 8.72 (1H, br s), 7.84-7.74 (2H, m), 7.96 (1H, s), 7.58 (1H, d, J 8.0 Hz), 7.48-7.25 (8H, m), 7.08-6.98 (3H, m), 5.16 (2H, s), 3.80 (2H, m), 3.53 (4H, m), 2.50 (4H, m); m/z: 483 [M+H]⁺.

Compound 23: N-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 9.71 (1H, s), 8.56 (1H, m), 8.20 (1H, d, J 8.0 Hz), 8.12 (1H, s), 7.84 (1H, dd, J 8.0, 2.0 Hz), 7.60-7.54 (3H, m), 7.26-7.18 (4H, m), 6.95 (2H, m), 5.29 (2H, s), 3.76 (2H, m), 3.46 (2H, s), 3.36 (2H, m), 2.60-2.27 (4H, m); m/z: 425 [M+H]⁺.

Compound 24: N-(4-(4-cyanophenyl)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 10.04 (1H, s), 8.67 (1H, m), 8.36 (1H, d, J 8.0 Hz), 7.97-7.88 (3H, m), 7.75-7.61 (6H, m), 7.29 (2H, m), 7.03 (2H, m), 3.84 (2H, m), 3.60-3.34 (4H, m), 2.49 (4H, m); m/z: 521 [M+H]⁺.

Compound 25: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-trifluoromethylphenyl)phenyl)picolinamide

¹H nmr (CDCl₃) δ 10.02 (1H, s), 8.68 (1H, m), 8.37 (1H, d, J 8.0 Hz), 7.95 (1H, d, J 9.0 Hz), 7.89 (2H, d, J 8.5 Hz), 7.71-7.61 (6H, m), 7.28 (2H, m), 7.04 (2H, m), 3.84 (2H, m), 3.60-3.38 (4H, m), 2.56 (2H, m), 2.43 (2H, m); m/z: 564 [M+H]⁺.

Compound 26: N-(4-benzoylphenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 10.15 (1H, s), 8.67 (1H, m), 8.35 (1H, d, J 8.0 Hz), 7.95 (1H, dd, J 8.0, 2.0 Hz), 7.90 (4H, m), 7.79 (2H, d, J 7.5 Hz), 7.59 (1H, m), 7.49 (2H, m), 7.29 (2H, m), 7.02 (2H, m), 3.83 (2H, m), 3.54 (2H, s), 3.47 (2H, m), 2.56 (2H, m), 2.43 (2H, m) m/z: 524 [M+H]⁺.

Compound 27: N-(4-benzyloxyphenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 9.75 (1H, s), 8.58 (1H, s), 2.27 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 8.0, 2.0 Hz), 7.62 (2H, d, J 9.0 Hz), 7.39-7.18 (7H, m), 6.96-6.90 (4H, m), 5.01 (2H, s), 3.76 (2H, m), 3.52-3.28 (4H, m), 2.60-2.24 (4H, m); m/z: 526 [M+H]⁺.

Compound 28: N-(4-bromophenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 9.93 (1H, s), 8.65 (1H, s), 8.33 (1H, d, J 8.0 Hz), 7.93 (1H, dd, J 8.0, 2.0 Hz), 7.68 (2H, d, J 9.0 Hz), 7.50 (2H, d, J 9.0 Hz), 7.28 (2H, m), 7.02 (2H, m), 3.82 (2H, m), 3.52 (2H, s), 3.42 (2H, m), 2.49 (4H, m); m/z: 497, 499 [M+H]⁺.

Compound 29: N-(4-(4-methoxyphenyl)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 9.96 (1H, s), 8.66 (1H, m), 8.36 (1H, d, J 8.0 Hz), 7.93 (1H, dd, J 8.0, 2.0 Hz), 7.83 (2H, d, J 9.0 Hz), 7.60-7.51 (4H, m), 7.29 (2H, m), 7.03 (2H, m), 6.97 (2H, d, J 9.0 Hz), 3.85 (5H, m), 3.60-3.36 (4H, m), 2.50 (4H, m); m/z: 526 [M+H]⁺.

Compound 30: (6-(4-benzylphenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

¹H nmr (CDCl₃) δ 8.26 (1H, s), 7.56 (1H, dd, J 9.0, 1.0), 7.32-7.15 (10H, m), 7.06-6.97 (3H, m), 6.77 (1H, d, J 8.5 Hz), 3.96 (2H, s), 3.66 (4H, m), 3.52 (2H, s), 2.47 (4H, m); m/z: 482 [M+H]⁺.

Compound 31: 4-((2-(5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)benzonitrile

m/z: 554 [M+H]⁺.

Compound 32: N-(4-(3-cyanophenyl)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 10.04 (1H, s), 8.67 (1H, s), 8.35 (1H, d, J 8.0 Hz), 7.95 (1H, dd, J 8.0, 2.0), 7.94-7.80 (3H, m), 7.63-7.52 (3H, m), 7.28 (2H, m), 7.02 (2H, m), 3.83 (2H, m), 3.53 (2H, s), 3.44 (2H, m), 2.48 (4H, m); m/z: 521 [M+H]⁺.

Compound 33: (6-(3-phenylphenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

¹H nmr (CDCl₃) δ 8.23 (1H, s), 7.56-7.47 (4H, m), 7.39-7.18 (9H, m), 6.93 (2H, t, J 9.0 Hz), 6.80 (1H, d, 8.5 Hz), 3.59 (4H, m), 3.43 (2H, s), 2.39 (4H, m)); m/z: 468 [M+H]⁺.

Compound 34: (4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-phenoxyphenylamino)pyridin-3-yl)methanone

¹H nmr (CDCl₃) δ 8.26 (1H, s), 7.58 (1H, dd, J 9.0, 2.0 Hz), 7.35-7.25 (6H, m), 7.12-6.97 (8H, m), 6.73 (1H, d, J 9.0 Hz), 3.66 (4H, m), 3.51 (2H, s), 2.46 (4H, m); m/z: 483 [M+H]⁺.

Compound 35: (6-(4-(4-cyanobenzylcarbamoyl)phenyl)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

¹H nmr (CDCl₃) δ 8.64 (1H, br s), 7.96 (2H, d, J 8.0 Hz), 7.83 (2H, d, J 8.0 Hz), 7.75-7.68 (2H, m), 7.56 (2H, d, J 8.0 Hz), 7.40 (2H, d, J 8.0 Hz), 7.26-7.19 (2H, m), 7.01-6.91 (3H, m), 4.65 (2H, d, J 6.0 Hz), 3.73 (2H, m), 3.47 (4H, m), 2.42 (4H, m); m/z: 535 [M+H]⁺.

Compound 36: (6-(4-(cyanobenzyl)piperidin-4-ylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

¹H nmr (CD₃OD) δ 8.06 (1H, s), 7.68 (2H, dd, J 8.0, 2.0 Hz), 7.44 (1H, m), 7.36-7.32 (2H, m), 7.06-6.98 (2H, m), 6.49 (2H, d, J 9.0 Hz), 3.68-3.56 (6H, m), 3.34 (2H, s), 2.84 (2H, m), 2.46 (4H, m), 2.20 (2H, m), 1.96 (2H, m), 1.60-1.47 (2H, m); m/z: 514 [M+H]⁺.

Compound 37: (6-(4-phenylphenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

¹H nmr (CDCl₃) δ 8.31 (1H, d, J 2.0 Hz), 7.65-7.55 (5H, m), 7.46-7.40 (4H, m), 7.36-7.25 (3H, m), 7.16 (1H, s), 7.01 (2H, t, J 9.0 Hz), 6.87 (1H, d, J 9.0 Hz), 3.68 (4H, m), 3.52 (2H, s), 2.48 (4H, m); n/z: 467 [M+H]⁺.

Compound 38: N⁵-(1-(4-cyanobenzyl)-1H-pyrazol-3-yl)-N²-(1-(4-cyanobenzyl)piperidin-4-yl)pyridine-2,5-dicarboxamide

¹H nmr (CDCl₃) δ 8.98 (1H, s), 8.57 (1H, s), 8.22 (2H, m), 7.92 (1H, m), 7.59-7.54 (4H, m), 7.46 (2H, m), 7.39 (1H, d, J 2.0 Hz), 7.21-7.16 (2H, m), 6.86 (1H, d, J 1.5 Hz), 5.21 (2H, s), 3.96 (1H, m), 3.57 (2H, s), 2.89-2.80 (2H, m), 2.23 (2H, m), 1.97 (2H, m), 1.67 (2H, m); m/z: 546 [M+H]⁺.

Compound 39: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(1H-pyrrol-3-yl)phenyl)picolinamide

¹H nmr (CDCl₃) δ 9.85 (1H, s), 8.58 (1H, s), 8.31 (1H, m), 8.27 (1H, d, J 8.0 Hz), 7.85 (1H, d, J 8.0, 2.0 Hz), 7.68 (2H, d, J 9.0 Hz), 7.48 (2H, d, J 9.0 Hz), 7.24-7.18 (2H, m), 7.02 (1H, m), 6.95 (2H, t, J 8.5 Hz), 6.77 (1H, m), 6.47 (1H, m), 3.76 (2H, m), 3.46-3.32 (4H, m), 2.48 (2H, m), 2.36 (2H, m); m/z: 485 [M+H]⁺.

Compound 40: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-morpholinophenyl)picolinamide

¹H nmr (CDCl₃) δ 9.74 (1H, s), 8.57 (1H, s), 8.26 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 2.0 Hz), 7.62 (2H, d, J 9.0 Hz), 7.22 (2H, m), 6.94 (2H, t, J 9.0 Hz), 6.88 (2H, d, J 9.0 Hz), 3.83-3.53 (6H, m), 3.45 (2H, s), 3.36 (2H, m), 3.08 (4H, m), 2.48 (2H, m), 2.35 (2H, m); m/z: 505 [M+H]⁺.

Compound 41: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)picolinamide

¹H nmr (CDCl₃) δ 9.74 (1H, s), 8.57 (1H, m), 8.25 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 8.0, 2.0), 7.60 (2H, d, J 9.0 Hz), 7.24-7.18 (2H, m), 6.97-6.87 (4H, m), 3.75 (2H, m), 3.45 (2H, s), 3.36 (2H, m), 3.19 (4H, m), 2.60 (4H, m), 2.48 (2H, m), 2.34 (5H, m); m/z: 518 [M+H]⁺.

Compound 42: (6-(3-(4-cyanobenzylcarbamoyl)phenyl)pyridin-3yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

¹H nmr (CDCl₃) δ 8.64 (1H, br s), 8.40 (1H, s), 8.07 (1H, d, J 8.0 Hz), 7.86 (1H, d, J 8.0 Hz), 7.77 (2H, m), 7.59-7.47 (3H, m), 7.41 (2H, d, J 8.0 Hz), 7.24-7.17 (2H, m), 6.95 (2H, t, J 9.0 Hz), 6.88 (1H, m), 4.66 (2H, d, J 6.0 Hz), 3.74 (2H, m), 3.45 (4H, m), 2.42 (4H, m); m/z: 535 [M+H]⁺.

Compound 43: N⁵-(1-(4-cyanobenzyl)-H-pyrazol-4-yl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)pyridine-2,5-dicarboxamide

¹H nmr (D₆-DMSO) δ 10.83 (1H, s), 9.08 (1H, s), 8.70 (1H, d, J 8.0 Hz), 8.43 (1H, dd, J 8.0, 2.0 Hz), 8.25 (1H, s), 8.13 (1H, d, J 8.5 Hz), 7.79 (4H, m), 7.67 (1H, s), 7.49 (2H, d, J 8.0 Hz), 7.33 (2H, d, J 8.0 Hz), 5.45 (2H, s), 3.80 (1H, m), 3.55 (2H, s), 2.76 (2H, m), 2.07 (2H, m), 1.71 (4H, m); m/z: 546 [M+H]⁺.

Compound 44: (6-(1-(4-fluorobenzyl)-1H-pyrazol-4-ylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

¹H nmr (CDCl₃) δ 8.15 (1H, d, J 2.0 Hz), 7.61 (1, 1H), 7.46 (1H, dd, J 8.0, 2.0 Hz), 7.42 (1H, s), 7.24-7.12 (4H, m), 6.99-6.90 (4H, m), 6.70 (1H, s), 6.45 (1H, d, J 8.5 Hz), 5.17 (2H, s), 3.57 (4H, m), 3.44 (2H, m), 2.39 (4H, m); m/z: 489 [M+H]⁺.

Compound 45: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-fluorobenzyl)-1H-pyrazol-4-ylamino)picolinamide

¹H nmr (CDCl₃) δ 7.92 (1H, d, J 3.0 Hz), 7.89 (1H, d, J 9.0 Hz), 7.62 (1H, d, J 8.5 Hz), 7.54 (2H, d, J 8.0 Hz), 7.44-7.38 (3H, m), 7.30 (1H, s), 7.19-7.13 (2H, m), 7.02-6.94 (3H, m), 5.49 (1H, s), 5.19 (2H, s), 3.98-3.84 (1H, m), 3.52 (2H, s), 2.76 (2H, m), 2.17 (2H, m), 1.93 (2H, m), 1.57 (2H, m); m/z: 511 [M+H]⁺.

Compound 46: (6-(1-(4-cyanobenzyl)piperidine-4-carboxamido)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

To a mixture of (4-(4-fluorobenzyl)piperazin-1-yl)(6-bromopyridin-3-yl)methanone (0.040 g, 0.11 mmol, 1.0 eq), 1-(4-cyanobenzyl)piperidine-4-carboxamide (0.028 g, 0.12, 1.1 eq), and N,N′-dimethylethylenediamine (0.012 mL, 0.11 mmol, 1.0 eq) was added anhydrous toluene (1.0 mL). This mixture was purged with argon for 5 minutes and copper(I)iodide (0.011 g, 0.058 mmol, 0.5 eq) and potassium carbonate (0.044 g, 0.23 mmol, 2.1 eq) were added. The reaction mixture was heated at 100° C. for 4.5 hours and then absorbed on silica gel. Purification by column chromatography (silica, 0-*5% MeOH—CH₂Cl₂) yielded a green solid (0.070 g). Further purification using preparative TLC (silica, 4% MeOH— CH₂Cl₂) provided Compound 46 as a white solid (0.040 g, 67%). ¹H nmr (D₆-DMSO) δ 10.64 (1H, s), 8.32 (1H, s), 8.10 (1H, d, J 8.5 Hz), 7.81-7.74 (3H, m), 7.53-7.46 (2H, m), 7.31 (2H, t, J 8.0 Hz), 7.12 (2H, t, J 9.0 Hz), 3.64-3.36 (9H, m), 2.79 (2H, m), 2.35 (m, 4H), 1.99-1.87 (2H, m), 1.79-1.54 (4H, m); m/z: 542 [M+H]⁺. More information about this type of coupling is provided in Wrona, Iwona E.; Gozman, Alexander; Taldone, Tony; Chiosis, Gabriela; Panek, James S. Journal of Organic Chemistry (2010), 75(9), 2820-2835.

¹H nmr (D₆-DMSO) δ 10.64 (1H, s), 8.32 (1H, s), 8.10 (1H, d, J 8.5 Hz), 7.81-7.74 (3H, m), 7.53-7.46 (2H, m), 7.31 (2H, t, J 8.0 Hz), 7.12 (2H, t, J 9.0 Hz), 3.64-3.36 (9H, m), 2.79 (2H, m), 2.35 (m, 4H), 1.99-1.87 (2H, m), 1.79-1.54 (4H, m); m/z: 542 [M+H]⁺.

Compound 47: N-(4-(4-cyanobenzylcarbamoyl)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 10.03 (1H, s), 8.58 (1H, s), 8.24 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 8.0, 2.0 Hz), 7.78 (4H, m), 7.57 (2H, d, J 8.0 Hz), 7.40 (2H, d, J 8.0 Hz), 7.26-7.19 (2H, m), 6.95 (2H, t, J 9.0 Hz), 6.68 (1H, m) 4.64 (2H, d, J 6.0 Hz), 3.76 (2H, m), 3.47 (2H, s), 3.37 (2H, m), 2.49 (2H, m), 2.36 (2H, m); m/z: 578 [M+H]⁺.

Compound 48: (6-(4-(4-cyanobenzylcarbamoyl)phenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

¹H nmr (CDCl₃) δ 8.25 (1H, s), 7.81 (1H, s), 7.70 (1H, d, J 9.0 Hz), 7.53-7.33 (8H, m), 7.28-7.23 (2H, m), 6.99 (2H, t, J 9.0 Hz), 6.73 (1H, d, J 8.5 Hz), 4.60 (2H, d, J 6.0 Hz), 3.60 (4H, m), 3.48 (2H, s), 2.43 (4H, m); m/z: 550 [M+H]⁺.

Compound 49: N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.52 (1H, s), 8.16 (1H, d, J 8.0 Hz), 7.86 (1H, d, J 8.0 Hz), 7.81-7.78 (1H, m), 7.23-7.07 (3H, m), 7.06-6.91 (4H, m), 4.20-3.88 (1H, m), 3.74 (2H, m), 3.44 (2H, s), 3.43 (2H, s), 3.33 (2H, m), 2.78 (2H, m), 2.47 (2H, m), 2.321 (2H, m), 2.16 (2H, m), 1.96 (2H, m), 1.62 (2H, m); m/z: 553 [M+H]⁺.

Compound 50: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(4-fluoro-3-methylbenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.51 (s, 1H), 8.16 (1H, d, J 8.0 Hz), 7.85 (1H, d, J 9.0 Hz), 7.79 (1H, d, J 8.0 Hz), 7.23-7.18 (2H, m), 7.10-7.01 (2H, m), 6.97-6.84 (3H, m), 3.99-3.88 (1H, m), 3.74 (2H, m), 3.44 (2H, s), 3.40 (2H, s), 3.33 (2H, m), 2.79 (2H, m), 2.47 (2H, m), 2.32 (2H, m), 2.20 (3H, s), 2.13 (1H, m), 1.94 (2H, m), 1.60 (3H, m); m/z: 549 [M+H]⁺.

Compound 51: N-(1-(4-chlorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CD₃OD) δ 8.67 (1H, m, major isomer), 8.63 (1H, m, minor isomer), 8.16 (1H, d, J 8.0 Hz), 8.00 (1H, dd, J 8.0, 2.0 Hz), 7.38-7.32 (2H, m), 7.09-7.00 (5H, m), 6.81 (2H, d, J 9.0 Hz), 4.10 (m), 3.80 (m), 3.57 (s), 3.45 (m), 3.30 (m), 2.96 (s), 2.58-2.44 (m), 1.94-1.60 (m), 1.39-1.28 (m); m/z: 546 [M+H]⁺.

Compound 52: N-(1-(4-chlorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.57 (1H, s), 8.21 (1H, d, J 8.0 Hz), 7.90 (1H, d, J 8.0 Hz), 7.84 (1H, dd, J 8.0, 2.0), 7.28-7.22 (6H, m), 6.99 (2H, m), 4.04-3.92 (1H, m), 3.79 (2H, m), 3.49 (2H, s), 3.46 (2H, s), 3.38 (2H, m), 2.81 (2H, m), 2.52 (2H, m), 2.37 (2H, m), 2.17 (2H, m), 1.98 (2H, m), 1.62 (2H, m); m/z: 551, 553 [M+H]⁺.

Compound 53: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-methylphenoxy)phenyl)picolinamide

¹H nmr (CDCl₃) δ 9.88 (1H, s), 8.64 (1H, s), 8.33 (1H, d, J 8.0 Hz), 7.91 (1H, dd, J 8.0, 2.0 Hz), 7.71 (2H, d, J 9.0 Hz), 7.30-7.24 (2H, m), 7.13 (2H, d, J 8.0 Hz), 7.03-6.96 (4H, m), 6.91 (2H, d, J 8.5 Hz), 3.82 (2H, m), 3.51 (2H, s), 3.42 (2H, m), 2.54 (2H, m), 2.41 (2H, m), 2.33 (3H, s); m/z: 526 [M+H]⁺.

Compound 54: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-methoxyphenoxy)phenyl)picolinamide

¹H nmr (CDCl₃) δ 9.87 (1H, m), 8.64 (1H, s), 8.32 (1H, d, J 8.0 Hz), 7.91 (1H, dd, J 8.0, 2.0 Hz), 7.69 (2H, d, J 9.0 Hz), 7.30-7.24 (2H, m), 7.03-6.95 (6H, m), 6.87 (2H, m), 3.80 (5H, m), 3.51 (2H, s), 3.42 (2H, m), 2.54 (2H, m), 2.41 (2H, m); m/z: 541 [M+H]⁺.

Compound 55: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(3-fluorophenoxy)phenyl)picolinamide

¹H nmr (CDCl₃) δ 9.86 (1H, s), 8.59 (1H, s), 8.26 (1H, d, J 8.0 Hz), 7.85 (1H, dd, J 8.0, 2.0 Hz), 7.70 (2H, d, J 9.0 Hz), 7.24-7.15 (3H, m), 7.00 (2H, d, J 9.0 Hz), 6.94 (2H, t, J 9.0 Hz), 6.74-6.60 (3H, m), 3.75 (2H, m), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m/z: 530 [M+H]⁺.

Compound 56: N-(4-(3-cyanophenoxy)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 9.90 (1H, s), 8.59 (1H, s), 8.27 (1H, d, J 8.0 Hz), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.74 (2H, d, J 9.0 Hz), 7.38-7.25 (2H, m), 7.24-7.14 (4H, m), 7.00 (2H, d, J 9.0 Hz), 6.94 (2H, t, J 8.5 Hz), 3.76 (2H, m), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.35 (2H, m); m/z: 537 [M+H]⁺.

Compound 57: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(3-methoxyphenoxy)phenyl)picolinamide

¹H nmr (CDCl₃) δ 9.84 (1H, s), 8.59 (1H, s), 8.26 (1H, d, J 8.0 Hz), 7.85 (1H, dd, J 8.0, 2.0 Hz), 7.67 (2H, d, J 9.0 Hz), 7.24-7.11 (3H, m), 7.01-6.91 (4H, m), 6.60-6.48 (3H, m), 3.76 (2H, m), 3.70 (3H, s), 3.45 (2H, s), 3.37 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m/z: 542 [M+H]⁺.

Compound 58: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(3-methylphenoxy)phenyl)picolinamide

¹H nmr (CDCl₃) δ 9.90 (1H, s), 8.65 (1H, s), 8.33 (1H, d, J 8.0 Hz), 7.92 (1H, dd, J 8.0, 2.0 Hz), 7.73 (2H, d, J 9.0 Hz), 7.31-7.25 (2H, m), 7.21 (1H, t, J 7.5 Hz), 7.06-6.96 (4H, m), 6.90 (2H, d, J 7.5 Hz), 6.82 (2H, m), 3.82 (2H, m), 3.51 (2H, s), 3.42 (2H, s), 2.54 (2H, m), 2.41 (2H, m), 2.32 (3H, s); m/z: 526 [M+H]⁺.

Compound 59: N-(4-(4-cyanophenoxy)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 9.91 (1H, s), 8.59 (1H, s), 8.27 (1H, d, J 8.5 Hz), 7.87 (1H, dd, J 8.0, 1.5 Hz), 7.76 (2H, d, J 9.0 Hz), 7.53 (2H, d, J 8.5 Hz), 7.24-7.18 (2H, m), 7.04 (2H, d, J 9.0 Hz), 6.98-6.91 (4H, m), 3.76 (2H, m), 3.45 (2H, s), 3.36 (2H, m), 2.49 (2H, m), 2.35 (2H, m); m/z: 537 [M+H]⁺.

Compound 60: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-fluorophenoxy)phenyl)picolinamide

¹H nmr (CDCl₃) δ 9.84 (1H, s), 8.58 (1H, s), 8.27 (1H, d, J 8.5 Hz), 7.88-7.84 (1H, m), 7.66 (2H, d, J 9.0 Hz), 7.24-7.18 (3H, m), 6.99-6.88 (7H, m), 3.76 (2H, m), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m/z: 530 [M+H]⁺.

Compound 61: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(pyridine-3-yl)phenyl)picolinamide

¹H nmr (CDCl₃) δ 9.97 (1H, s), 8.80 (1H, s), 8.61 (1H, s), 8.51 (1H, d, J 5.0 Hz), 7.90-7.80 (4H, m), 7.56 (2H, d, J 8.5 Hz), 7.33-7.27 (1H, m), 7.25-7.18 (2H, m), 6.95 (2H, t, J 8.5 Hz), 3.76 (2H, m), 3.45 (2H, s), 3.37 (2H, m), 2.49 (2H, m), 2.35 (2H, m); m/z: 497 [M+H]⁺.

Compound 62: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(thiophen-3-yl)phenyl)picolinamide

¹H nmr (CDCl₃) δ 9.91 (1H, s), 8.59 (1H, m), 8.28 (1H, d, J 8.0 Hz), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.75 (2H, d, J 8.5 Hz), 7.56 (2H, d, J 8.5 Hz), 7.38-7.31 (2H, m), 7.24-7.16 (3H, m), 6.94 (2H, t, J 8.5 Hz), 3.76 (2H, m), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.34 (2H, m); n/z: 502 [M+H]⁺.

Compound 63: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-(6-(4-cyanophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 9.89 (1H, s), 8.60 (1H, m), 8.40 (1H, d, J 2.5 Hz), 8.35 (1H, dd, J 9.0, 3.0 Hz), 8.26 (1H, dd, J 8.5, 1.0 Hz), 7.88 (1H, dd, J 8.0, 2.0 Hz), 7.61 (2H, d, J 9.0 Hz), 7.25-7.13 (4H, m), 7.00 (1H, d, J 9.0 Hz), 6.94 (2H, t, J 8.5 Hz), 3.76 (2H, m), 3.45 (2H, s), 3.35 (2H, m), 2.48 (2H, m), 2.35 (2H, m); m/z: 538 [M+H]⁺.

Compound 64: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-(6-(3-cyanophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 9.87 (1H, s), 8.60 (1H, m), 8.36 (2H, m), 8.26 (1H, d, J 8.5 Hz), 7.87 (1H, dd, J 8.0, 2.0 Hz), 7.46-7.31 (3H, m), 7.23-7.18 (3H, m), 7.02-6.90 (3H, m), 3.76 (2H, m), 3.45 (2H, s), 3.35 (2H, m), 2.48 (2H, m), 2.35 (2H, m); m/z: 538 [M+H]⁺.

Compound 65: 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 9.83 (1H, s), 8.58 (1H, m), 8.37-8.21 (4H, m), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.24-7.17 (2H, m), 7.05-6.86 (6H, m), 3.75 (2H, m), 3.44 (2H, s), 3.34 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m/z: 531 [M+H]⁺.

Compound 66: 5-(4-(4-cyano-2-methoxyphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.54 (1H, m), 8.18 (1H, d, J 8.0 Hz), 7.87-7.80 (2H, m), 7.55 (2H, d, J 8.5 Hz), 7.39 (2H, d, J 8.0 Hz), 7.21-7.15 (1H, m), 7.05 (1H, m), 6.87 (1H, d, J 8.0 Hz), 4.66-4.58 (1H, m), 3.97-3.78 (6H, m), 3.60 (1H, m), 3.50 (2H, s), 3.41 (2H, m), 3.31 (1H, m), 2.76 (2H, m), 2.16 (2H, m), 2.20-1.57 (4H, m), 1.63-1.52 (2H, m); m/z: 580 [M+H]⁺.

Compound 67: 5-(4-(4-fluoro-4-fluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 9.83 (1H, s), 8.64 (1H, s), 8.36-8.24 (3H, m), 8.11-8.05 (2H, m), 7.92 (1H, dd, J 8.0, 2.0 Hz), 7.11-6.97 (6H, m), 6.89 (1H, d, J 9.0 Hz), 4.62 (1H, m), 3.70-3.41 (3H, m), 2.36-1.91 (4H, m); m/z: 562 [M+H]⁺.

Compound 68: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluoro-4-fluorobenzoyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.57 (1H, s), 8.19 (1H, d, J 8.0 Hz), 8.09-8.04 (2H, m), 7.88-7.82 (2H, m), 7.54 (2H, d, J 8.5 Hz), 7.39 (2H, d, J 8.0 Hz), 7.08 (2H, t, J 8.5 Hz), 4.60 (1H, m), 3.99-3.90 (1H, m), 3.60-3.30 (4H, m), 2.75 (2H, m), 2.28-2.07 (6H, m), 1.95 (3H, m), 1.65-1.53 (2H, m); m/z: 573 [M+H]⁺.

Compound 69: 5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 9.85 (1H, s), 8.62 (1H, s), 8.37-8.25 (3H, m), 7.92-7.85 (3H, m), 7.06-6.99 (4H, m), 6.90 (3H, m), 4.62 (1H, m), 3.81 (3H, s), 3.72 (1H, m), 3.49 (1H, s), 3.28-2.98 (2H, m), 1.97 (1H, m), 1.77 (3H, m); m/z: 556 [M+H]⁺.

Compound 70: 5-(4-(4-methoxyphenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 9.84 (1H, s), 8.61 (1H, s), 8.35-8.25 (2H, m), 7.89 (1H, dd, J 8.0, 2.0 Hz), 7.06-7.01 (4H, m), 6.90 (1H, d, J 9.0 Hz), 6.83-6.75 (4H, m), 4.43 (1H, m), 3.84 (2H, m), 3.70 (3H, m), 3.31 (1H, m), 1.93 (2H, m), 1.79 (2H, m); m/z: 544 [M+H]⁺.

Compound 71: trans-N-(4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.53 (1H, s), 8.18 (1H, d, J 8.0 Hz), 7.86-7.80 (2H, m), 7.51 (2H, d, J 9.0 Hz), 7.00 (2H, t, J 8.5 Hz), 4.27 (1H, m), 4.07-3.40 (7H, m), 2.65 (4H, m), 2.13 (4H, m), 1.68-1.57 (2H, m), 1.49-1.38 (2H, m); m/z: 543 [M+H]⁺.

Compound 94: (4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-phenylpiperazine-1-carbonyl)pyridin-2-yl)methanone

To a suspension of pyridine-2,6-dicarboxylic acid (0.200 g, 1.20 mmol, 1.0 eq) in tetrahydrofuran (6.0 mL) was added 4-fluorobenzylpiperazine (0.116 g, 0.60 mmol, 0.5 eq). Triethylamine (0.33 mL, 2.40 mmol, 2.0 eq) was added followed by HATU (0.319 g, 0.84 mmol, 0.7 eq) and the reaction was stirred at room temperature for 14 hours. The reaction mixture was diluted with methanol (3.0 mL) and (trimethylsilyl)diazomethane (2.0 mL of a 2M solution in hexane, 4.00 mmol). The reaction mixture was stirred at room temperature for 30 minutes before concentrating under reduced pressure. The residue was partitioned between NaHCO₃ (50 mL) and EtOAc (50 mL). The organics were washed with brine (50 mL), dried (Na₂SO₄) and concentrated under reduced pressure. Column chromatography (silica, 2→5% MeOH—CH₂Cl₂) yielded methyl 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate (0.214 g, 50%) as a white solid; m/z: 358 [M+H]⁺. To a solution of the methyl 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate (0.214 g, 0.60 mmol, 1.0 eq) in tetrahydrofuran (4.0 mL) was added a solution of lithium hydroxide monohydrate (0.050 g, 1.20 mmol, 2.0 eq) in water (3.0 mL). The reaction was stirred at room temperature for 25 minutes before neutralizing with HCl (approximately 0.6 mL of a 2M solution). The reaction mixture was concentrated to dryness to yield 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinic acid, which was used without further purification; m/z: 344 [M+H]⁺. To a solution of the crude 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinic acid (approximately 0.200 mmol, 1.0 eq) and triethylamine (0.083 mL, 0.600 mmol, 3.0 eq) in dimethylformamide (2.0 mL) was added 1-phenylpiperazine (0.036 mL, 0.240 mmol, 1.2 eq). HATU was added and the reaction shaken at room temperature for 2.5 hours before partitioning between EtOAc (50 mL) and NaHCO₃-water (1:1, 50 mL). The organics were further washed with brine (50 mL), water (50 mL) and brine (50 mL) before drying (Na₂SO₄) and concentrating under reduced pressure. Column chromatography (silica, 3→7% MeOH—CH₂Cl₂) yielded Compound 94 as a colourless oil; ¹H nmr (CDCl₃) δ 7.92 (1H, t, J 7.5 Hz, pyH-4), 7.73 (1H, d, J 8.0 Hz, pyH-3 or pyH-5), 7.70 (1H, d, J 7.5 Hz, pyH-3 or pyH-5), 7.33-7.22 (4H, m, 2H of C₆H₄F and 2H of C₆H₅), 7.01-6.90 (5H, m, 2H of C₆H₄F and 3H of C₆H₅), 3.97 (2H, dd, J 5.5, 5.0 Hz, 2H of piz), 3.81 (2H, dd, J 5.0, 4.5 Hz, 2H of piz), 3.74 (2H, t, J 5.0 Hz, 2H of piz), 3.55 (2H, dd, J 5.0, 4.5 Hz, 2H of piz), 3.46 (2H, s, CH ₂C₆H₅), 3.29 (2H, t, J 5.0 Hz, 2H of piz), 3.17 (2H, dd, J 5.5, 4.5 Hz, 2H of piz), 2.52 (2H, t, J 5.0 Hz, 2H of piz), 2.39 (2H, dd, 5.0, 4.5 Hz, 2H of piz); m/z: 488 [M+H]⁺.

Compound 140: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3,5-difluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.58 (1H, br s, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, d, J 9.0 Hz, NH), 7.86 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.87 (2H, d, J 6.5 Hz, H-2 and H-6 of C₆H₃F₂), 6.70 (1H, t, J 9.0 Hz, H-4 of C₆H₃F₂), 4.00 (1H, m, pipH-4), 3.82 (2H, m, 2H of piz), 3.56 (2H, s, 1×CH₂Ar), 3.51 (2H, s, 1×CH₂Ar), 3.41 (2H, m, 2H of piz), 2.81 (2H, m, 2H of pip), 2.55 (2H, m, 2H of piz), 2.40 (2H, m, 2H of piz), 2.22 (2H, t, J 11.0 Hz, 2H of pip), 2.01 (2H, m, 2H of pip), 1.64 (2H, m, 2H of pip); m/z: 560 [M+H]⁺.

Compound 141: 5-(4-(4-carbamoylbenzyl)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

¹H nmr (D₆-DMSO) δ 8.65 (2H, m, NH, 1×pyH), 8.04 (1H, m, 2×pyH), 7.81 (1H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄CONH₂), 7.78 (2H, d, J 8.0 Hz, 2H of C₆H₄CN or C₆H₄CONH₂), 7.49 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.01 (2H, d, J 9.0 Hz, 2H of C₆H₄CONH₂), 4.75 (1H, m, oxypipH-4), 4.09 (1H, m, 1H of oxypipH-2, H-6), 3.80 (1H, m, pipH-4), 3.54 (2H, s, CH₂C₆H₄CN), 3.48 (2H, m, 2H of oxypipH-2, H-6), 3.25 (1H, m, 1H of oxypipH-2, H-6), 2.75 (2H, m, 2H of pipH-2, H-6), 2.06 (3H, m, 2H of pipH-2, H-6, 1H of oxypipH-3, H-5), 1.91 (1H, m, 1H of oxypipH-3, H-5), 1.71 (6H, m, 4H of pipH-3, H-5, 2H of oxypipH-3, H-5); m/z: 568 [M+H]⁺.

Compound 142: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-((4-fluorophenyl)hydroxy)methyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.56 (1H, br s, pyH-6), 8.21 (1H, d, J 7.0 Hz, pyH-3), 7.91 (1H, d, J 8.5 Hz, NH), 7.85 (1H, m, pyH-4), 7.61 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.26 (2H, m, 2H of C₆H₄F), 7.04 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 4.75 (1H, m, 1H of BnpipH-2, H-6), 4.43 (1H, d, J 7.0 Hz, CH(OH)C₆H₄F), 3.99 (1H, m, pipH-4), 3.66 (1H, m, 1H of BnpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.01 (1H, m, 1H of BnpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6) 2.71 (1H, m, 1H of BnpipH-2, H-6), 2.22 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.00 (2H, m, 2H of pipH-3, H-5), 1.86 (1H, m, BnpipH-4), 1.62 (2H, m, 2H of pipH-3, H-5), 1.44-1.30 (4H, m, 4H of BnpipH-3, H-5); m/z: 556 [M+H]⁺.

Compound 143: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxyphenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, d, J 1.5 Hz, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.87 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 6.82 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 4.47 (1H, m, 1H of oxypip), 4.00 (1H, m, pipH-4), 3.88 (2H, m, 2H of oxypip), 3.77 (3H, s, OCH₃), 3.63 (1H, m, 1H of oxypip), 3.56 (2H, s, CH ₂C₆H₄CN), 3.35 (1H, m, 1H of oxypip), 2.81 (2H, m, 2H of pip), 2.23 (2H, dd, J 11.0, 10.0 Hz, 2H of pip), 2.01 (4H, m, 2H of pip, 2H of oxypip), 1.82 (2H, m, 2H of oxypip), 1.63 (2H, m, 2H of pip); m/z: 555 [M+H]⁺.

Compound 144: N2-(2-(4-cyanobenzyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N5-(4-fluorobenzyl)pyridine-2,5-dicarboxamide

¹H nmr (CDCl₃) δ 9.86 (1H, s, IsoqH-8), 8.99 (1H, d, J 1.0 Hz, pyH-6), 8.28 (1H, d, J 8.0 Hz, pyH-3), 8.22 (1H, dd, J 8.0, 1.5 Hz, pyH-4), 7.51 (2H, d, J 8.0 Hz, 2H of C₄H₄CN), 7.51 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.42 (1H, dd, J 8.5, 1.5 Hz, IsoqH-6), 7.33 (2H, m, 2H of C₆H₄F), 7.12 (1H, d, J 8.5 Hz, IsoqH-5), 7.04 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.71 (1H, t, J 5.5 Hz, NH), 4.63 (2H, d, J 6.0 Hz, NHCH₂C₆H₄F), 3.72 (2H, s, IsoqH-1 of CH₂C₆H₄CN), 3.62 (2H, s, IsoqH-1 or CH₂C₆H₄CN), 2.89 (2H, t, J 5.5 Hz, IsoqH-3 or IsoqH-4), 2.75 (2H, t, J 6.0 Hz, IsoqH-3 or H-4); m/z: 520 [M+H]⁺.

Compound 145: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methylbenzyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.56 (1H, s, pyH-6), 8.21 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, d, J 8.5 Hz, NH), 7.84 (1H, dd, J 8.0, 1.5 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.09 (2H, d, J 8.0 Hz, 2H of C₆H₄CH₃), 7.02 (2H, d, J 8.0 Hz, 2H of C₆H₄CH₃), 4.69 (1H, m, 1H of BnpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.60 (1H, m, 1H of BnpipH-2, H-6), 3.58 (2H, s, CH₂C₆H₄CN), 3.00 (1H, m, 1H of BnpipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.74 (1H, m, 1H of BnpipH-2, H-6), 2.53 (2H, m, CH₂C₆H₄CH₃), 2.04 (3H, s, CH₃), 2.24 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.01 (2H, m, 2H of pipH-3, H-5), 1.79-1.63 (4H, m, 2H of pipH-3, H-5, BnpipH-4′, 1H of BnpipH-3, H-5), 1.31-1.13 (3H, m, 3H of BnpipH-3, H-5); m/z: 537 [M+H]⁺.

Compound 146: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3-fluoro-4-methoxybenzyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.56 (1H, m, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.5 Hz, NH), 7.85 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.20 (1H, t, 8.0 Hz, 1×ArH), 6.73 (1H, dd, J 8.0, 7.0 Hz, 1×ArH), 6.68 (1H, br s, 1×ArH), 4.69 (1H, m, 1H of Bnpip), 4.00 (1H, m, pipH-4), 3.79 (3H, s, OCH₃), 3.62 (1H, m, 1H of Bnpip), 3.56 (2H, s, CH₂C₆H₄CN), 3.01 (1H, m, 1H of Bnpip), 2.81 (2H, m, 2H of pip), 2.75 (1H, m, 1H of Bnpip), 2.55 (2H, t, J 6.0 Hz, CH₂C₆H₃FOCH₃), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H of pip), 2.01 (2H, m, 2H of pip), 1.82 (2H, m, 2H of Bnpip), 1.64 (2H, m, 2H of pip), 1.33-1.18 (3H, m, 3H of Bnpip); m/z: 570 [M+H]⁺.

Compound 147: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3-methoxybenzyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.56 (1H, br s, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.5 Hz, NH), 7.84 (1H, br d, J 8.0 Hz, pyH-4), 7.61 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.85 (4H, m, 4H of C₆H₄OCH₃), 4.69 (1H, m, 1H of BnpipH-2, H-6), 3.99 (1H, m, pipH-4), 3.86 (3H, s, OCH₃), 3.62 (1H, m, 1H of BnpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.02 (1H, m, 1H of BnpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.75 (1H, m, 1H of BnpipH-2, H-6), 2.51 (2H, m, CH ₂C₆H₄OCH₃), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.01 (2H, m, 2H of pipH-3, H-5), 1.77 (2H, m, 2H of BnpipH-3, H-4, H-5), 1.64 (2H, m, 2H of pipH-3, H-5), 1.30-1.16 (3H, m, 3H of BnpipH-3, H-4, H-5); m/z: 552 [M+H]⁺.

Compound 148: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, s, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.98 (2H, dd, J 9.5, 8.0 Hz, 2H of C₆H₄F), 6.86 (2H, m, 2H of C₆H₄F), 4.52 (1H, m, oxypipH-4), 4.01 (1H, m, pipH-4), 3.88 (2H, m, 2H of oxypipH-2, H-6), 3.64 (1H, m, 1H of oxypipH-2, H-6), 3.58 (2H, s, CH₂C₆H₄CN), 3.32 (1H, m, 1H of oxypipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.01 (3H, m, 2H of pipH-3, H-5, 1H of oxypipH-3, H-5), 1.83 (3H, m, 3H of oxypipH-3, H-5), 1.66 (2H, m, 2H of pipH-3, H-5); m/z: 542 [M+H]⁺.

Compound 149: N2-(1-(4-cyanobenzyl)piperidin-4-yl)-N5-(2-(4-fluorophenoxy)ethyl)pyridine-2,5-dicarboxamide

¹H nmr (CDCl₃) δ 8.94 (1H, s, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 8.19 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.95 (1H, d, J 8.5 Hz, NHpip), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.98 (2H, dd, J 9.5, 8.0 Hz, 2H of C₆H₄F), 6.85 (2H, dd, J 9.5, 4.5 Hz, 2H of C₆H₄F), 6.67 (1H, br s, NHCH₂CH₂O), 4.13 (2H, t, J 5.0 Hz, NHCH₂CH ₂O), 4.00 (1H, m, pipH-4), 3.89 (2H, q, J 5.5 Hz, NHCH ₂CH₂O), 3.56 (2H, s, CH ₂C₆H₄CN), 2.81 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.5, 11.0 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.69 (2H, m, 2H of pipH-3, H-5) m/z: 502 [M+H]⁺.

Compound 150: N-(cis-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.58 (1H, m, pyH-6), 8.23 (1H, dd, J 8.0, 1.0 Hz, pyH-3), 7.99 (1H, d, J 8.5 Hz, NH), 7.86 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.58 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.26 (2H, m, 2H of C₆H₄F), 7.00 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 4.59 (1H, br s, cHexH-1), 4.10 (1H, m, cHexH-4), 3.80 (2H, m, 2H of piz), 3.50 (2H, s, CH2C6H4F), 3.39 (2H, m, 2H of piz), 2.53 (2H, m, 2H of piz), 2.38 (2H, m, 2H of piz), 2.06 (2H, m, 2H of cHexH-2, H-6), 1.90-1.72 (4H, m, 2H of cHexH2, H-6, 2H of cHexH-3, H-5), 1.24 (2H, m, 2H of cHexH-3, H-5); m/z: 542 [M+H]⁺.

Compound 151: N-(trans-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorobenzoyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 8.02-7.96 (3H, m, 2H of C₆H₄F, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.58 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.16 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 4.66 (1H, m, 1H of pipH-2, H-6), 4.60 (1H, br s, cHexH-1), 4.10 (1H, m, cHexH-4), 3.76 (1H, m, 1H of pipH-2, H-6), 3.54 (1H, m, pipH-4), 3.24 (1H, m, 1H of pipH-2, H-6), 3.11 (1H, m, 1H of pipH-2, H-6), 2.07 (3H, m, 3H of cHexH-2, H-6), 1.90-1.79 (8H, m, 1H of cHexH-2, H-6, 3H of cHexH-3, H-5, 4H of pipH-3, H-5), 1.25 (1H, m, 1H of cHexH-3, H-5); m/z: 555 [M+H]⁺.

Compound 152: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorobenzyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.48 (1H, br s, pyH-6), 8.17 (1H, d, J 8.0 Hz, NH or pyH-3), 7.87 (1H, d, J 7.5 Hz, NH or pyH-3), 7.80 (1H, m, pyH-4), 7.60 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆ H ₄CN), 7.03 (2H, m, 2H of C₆H₄F), 6.93 (2H, m, 2H of C₆H₄F), 4.52 (1H, br s, 1H of Bnpip), 4.02 (1H, m, pipH-4), 3.57 (2H, s, CH ₂C₆H₄CN), 2.95 (1H, m, 1H of Bnpip), 2.81 (2H, m, 2H of pip), 2.68 (1H, dd, J 13.0, 10.5 Hz, 1H of Bnpip), 2.50 (1H, m, 1H of Bnpip), 2.26 (2H, td, J 11.5, 2.0 Hz, 2H of pip), 2.04 (2H, m, 2H of pip), 1.90-1.58 (5H, m, 2H of pip, 3H of Bnpip), 1.27 (2H, m, 2H of Bnpip); m/z: 541 [M+H]⁺. ** 2H of Bnpip missing, probably due to broadness of the peak in the 3-5 region **

Compound 153: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(2-(4-fluorobenzyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.19 (1H, br s, pyH-6), 8.10 (1H, d, J 7.5 Hz, 1H of NH, pyH-3 or pyH-4), 7.86 (1H, d, J 8.0 Hz, 1H of NH, pyH-3 or pyH-4), 7.60 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.05 (2H, m broad, 2H of C₆H₄F), 6.96 (2H, t, J 8.0 Hz, 2H of C₆H₄F), 4.00 (1H, m, pipH-4), 3.57 (2H, s, CH ₂C₆H₄CN), 3.08 (2H, m, 2H of Bnpip), 2.80 (3H, m, 2H of pip, 1H of Bnpip), 2.25 (2H, m, 2H of pip), 2.02 (2H, m, 2H of pip), 1.76-1.60 (8H, m, 2H of pip, 6H of Bnpip); m/z: 540 [M+H]⁺. **2H of Bnpip not showing up, probably too broad to observe**

Compound 154: 5-(4-(4-chlorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, dd, J 8.0, 0.5 Hz, pyH-3), 7.94-7.87 (4H, m, NH, pyH-4, 2H of C₆H₄Cl), 7.61 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.46 (4H, m, 2H of C₆H₄CN, 2H of C₆H₄Cl), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.77 (1H, m, 1H of BzpipH-2, H-6), 3.58 (2H, s, CH ₂C₆H₄CN), 3.53 (1H, m, BzpipH-4), 3.17 (2H, m 2H of BzpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, t, J 10.5 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of BzpipH-3, H-5), 1.82 (2H, m, 2H of pipH-3, H-5), 1.71-1.61 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5); m/z: 570 [M+H]⁺.

Compound 155: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3-cyanophenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.39 (1H, t, J 7.5 Hz, 1H of OC₆H₄CN), 7.26 (1H, m, 1H of OC₆H₄CN), 7.14 (2H, m, 2H of OC₆H₄CN), 4.65 (1H, m, PhoxypipH-4), 4.01 (1H, m, pipH-4), 3.90 (2H, m, 2H of PhoxypipH-2, H-6), 3.63 (1H, m, 1H of PhoxypipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.39 (1H, m, 1H of PhoxypipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.04-1.70 (6H, m, 2H of pipH-3, H-5, PhoxypipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m/z: 549 [M+H]⁺.

Compound 156: 5-(4-(3-chloro-4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, m, NH), 7.89 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.59 (1H, d, J 9.0 Hz, H-5 or H-6 of C₆H₃ClCN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.03 (1H, d, J 2.0 Hz, H-2 of C₆H₃ClCN), 6.87 (1H, dd, J 8.5, 2.0 Hz, H-5 or H-6 of C₆H₃ClCN), 4.69 (1H, m, PhoxypipH-4), 4.01 (1H, m, pipH-4), 3.91 (2H, m, 2H of PhoxypipH-2, H-6), 3.62 (1H, m, 1H of PhoxypipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.42 (1H, m, 1H of PhoxypipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.04-1.69 (6H, m, 2H of pipH-3, H-5, PhoxypipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m/z: 583, 585 [M+H]⁺.

Compound 157: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.94-7.87 (2H, m, NH, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.55 (2H, m, 2H of C₆H₄CF₃), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.97 (2H, d, J 9.0 Hz, 2H of C₆H₄CF₃), 4.70 (1H, m, 1H of Phoxypip), 4.01 (1H, m, 1H of Phoxypip or pipH-4), 3.95-3.87 (1H, m, 1H of Phoxypip or pipH-4), 3.64 (1H, m, 1H of Phoxypip), 3.58 (2H, s, CH ₂C₆H₄CN), 3.50 (1H, m, 1H of Phoxypip), 3.35 (1H, m, 1H of Phoxypip), 2.83 (2H, m, 2H of pip), 2.24 (2H, t, J 11.0 Hz, 2H of pip), 2.14-1.84 (6H, m, 2H of pip, 4H of Phoxypip), 1.65 (2H, m, 2H of pip); m/z: 592 [M+H]⁺.

Compound 158: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3,4-difluorophenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, m, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.07 (1H, q, J 9.5 Hz, H-5 of C₆H₃F₂), 6.74 (1H, m, H-1 of C₆H₃F₂), 6.61 (1H, m, H-6 of C₆H₃F₂), 4.51 (1H, m, PhoxypipH-4), 4.01 (1H, m, pipH-4), 3.88 (2H, m, 2H of PhoxyH-2, H-6), 3.63 (1H, m, 1H of PhoxypipH-2, H-6), 3.56 (2H, s, CH _(—)2C₆H₄CN), 3.37 (1H, m, 1H of PhoxypipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.04-1.84 (6H, m, 2H of pipH-3, H-5, 4H of PhoxypipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m/z: 560 [M+H]⁺.

Compound 159: N-(1-(4-cyanobenzyl)piperidin-4-yl)-3-(5,20-dioxo-24-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-7,10,13,16-tetraoxa-4,19-diazatetracos-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide

Hydrogen chloride (0.054 mL of a 4.0M solution in dioxane, 0.216 mmol, 5.0 eq) was added to a solution of Compound 164 (see below) (0.030 g, 0.043 mmol, 1.0 eq) in dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 90 minutes before removing the solvent under a stream of nitrogen. The residue was dried under vacuum to provide 3-(3-aminoprop-1-ynyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide trihydrochloride, which was used without further purification; m/z 594 [M+H]⁺. To a suspension of the 3-(3-aminoprop-1-ynyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide trihydrochloride (0.043 mmol, 1.0 eq) in dichloromethane (1.0 mL) was added triethylamine (0.018 mL, 0.129 mmol, 3.0 eq) forming a brown solution, 15-[(D)-(+)-Biotinylamino]-4,7,10,13-tetraoxapentadecanoic acid (0.023 g, 0.047 mmol, 1.1 eq) and HATU (0.018 g, 0.047 mmol, 1.1 eq) were added followed by dimethylaminopyridine (0.005 g, 0.043 mmol, 1.0 eq). The reaction was stirred at room temperature for 3 hours before pouring into water (20 mL). The organics were extracted with CH₂Cl₂ (3×25 mL). The combined organics were washed with brine (35 mL), dried (Na₂SO₄) and concentrated under reduced pressure. The crude material was purified by RP-HPLC to provide Compound 159; m/z 1068 [M+H]⁺.

Compound 160: 5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

To a solution of 5-(methoxycarbonyl)pyridine-2-carboxylic acid (0.209 g, 1.18 mmol, 1.0 eq) and 1-(4-methoxybenzyl)piperidine dihydrochloride (0.373 g, 1.27 mmol, 1.1 eq) in dimethylformamide (10 mL) was added triethylamine (0.40 mL, 2.89 mmol, 2.5 eq) followed by HATU (0.528 g, 1.39 mmol, 1.2 eq). The reaction was stirred at room temperature for 2 days before partitioning between EtOAc (100 mL) and water (80 mL). The organics were further washed with brine (80 mL), water (80 mL) and brine (80 mL), before drying (Na₂SO₄) and concentrating under reduced pressure to yield methyl 6-(1-(4-methoxybenzyl)piperidin-4-ylcarbamoyl)nicotinate as a white solid (0.378 g, 84%) which was used without further purification; ¹H nmr (CDCl₃) δ 9.13 (1H, m, pyH-6), 8.43 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.98 (1H, d, J 7.5 Hz, NH), 7.26 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 6.87 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 4.01 (1H, m, pipH-4), 3.98 (3H, s, 1×OCH₃), 3.80 (3H, s, 1×OCH₃), 3.53 (2H, s, CH ₂C₆H₄OCH₃), 2.90 (2H, m, 2H of pip), 2.24 (2H, dd, J 11.0, 10.0 Hz, 2H of pip), 2.02 (2H, m, 2H of pip), 1.69 (2H, m, 2H of pip); m/z 384 [M+H]⁺. To a solution of the methyl 6-(1-(4-methoxybenzyl)piperidin-4-ylcarbamoyl)nicotinate (0.378 g, 0.987 mmol, 1.0 eq) in tetrahydrofuran (6 mL) and methanol (3 mL) was added a solution of lithium hydroxide monohydrate (0.166 g, 3.948 mmol, 4.0 eq) in water (3 mL). The reaction mixture was stirred at room temperature for 30 minutes before neutralizing with HCl (approximately 2.0 mL of a 2M solution). The reaction was concentrated to dryness to yield 6-(1-(4-methoxybenzyl)piperidin-4-ylcarbamoyl)nicotinic acid as a white solid, which was used without purification. To a mixture of the 6-(1-(4-methoxybenzyl)piperidin-4-ylcarbamoyl)nicotinic acid (0.036 g, 0.098 mmol, 1.0 eq), 4-fluorobenzoylpiperidine hydrochloride (0.029 g, 0.117 mmol, 1.2 eq), and triethylamine (0.034 mL, 0.244 mmol, 2.5 eq) in dimethylformamide (1.0 eq) was added HATU (0.041 g, 0.244 mmol, 1.1 eq). The reaction was shaken at room temperature for 3 hours before adding water (5 mL). A gum formed, which was dissolved in EtOAc-CH₂Cl₂ (4:1, 50 mL). The solution was washed with NaHCO₃-water (1:1, 50 mL), brine (50 mL), water (50 mL) and brine (50 mL). The organics were dried (Na₂SO₄) and concentrated under reduced pressure. Column chromatography (silica, 3→7% MeOH—CH₂Cl₂) yielded Compound 160 as a colourless oil (0.037 g, 68%); ¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.98 (2H, dd, J 8.5, 5.5 Hz, 2H of C₆H₄F), 7.91 (1H, m, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.24 (2H, d, 2H of C₆H₄OCH₃), 7.16 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.86 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 4.66 (1H, m, BzpipH-4), 3.99 (1H, m, pipH-4), 3.80 (3H, s, OCH₃), 3.77 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, 1H of BzpipH-2, H-6), 3.48 (2H, s, CH2C₆H₄OCH₃), 3.21-3.11 (2H, m, 2H of BzpipH-2, H-6), 2.86 (2H, m, 2H of pipH-2, H-6), 2.19 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.00 (2H, m, 2H of pipH-3, H-5), 1.82 (4H, m, BzpipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m/z: 559 [M+H]⁺.

Compound 161: 5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, m, NH), 7.88 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.24 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 6.98 (2H, dd, J 9.0, 8.5 Hz, 2H of C₆H₄F), 6.86 (4H, m, 2H of C₆H₄F, 2H of C₆H₄OCH₃), 4.51 (1H, m, PhOpipH-4), 4.00 (1H, m, pipH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.80 (3H, s, OCH3), 3.63 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH ₂C₆H₄OCH₃), 3.34 (1H, m, 1H of PhOpipH-2, H-6), 2.87 (2H, m, 2H of pipH-2, H-6), 2.20 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.06-1.90 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.83 (2H, m, 2H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 547 [M+H]⁺.

Compound 162: 5-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.59 (1H, d, J 1.0 Hz, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.90 (1H, m, NH), 7.87 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.59 (2H, d, J 9.0 Hz, 2H of C₆H₄CN or C₆H₄OCH₃), 7.23 (2H, d, J 9.0 Hz, 2H of C₆H₄CN or C₆H₄OCH₃), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN or C₆H₄OCH₃), 6.86 (2H, d, J 9.0 Hz, 2H of C₆H₄CN or C₆H₄OCH₃), 4.70 (1H, m, PhOpipH-4), 3.99 (1H, m, pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.80 (3H, s, OCH₃), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.48 (2H, s, CH₂C₆H₄OCH₃), 3.41 (1H, m, 1H of PhOpipH-2, H-6), 2.87 (2H, m, 2H of pipH-2, H-6), 2.19 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.04-1.82 (6H, m, 2H of pipH-3, H-5 and 4H of PhOpipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m/z: 555 [M+H]⁺.

Compound 163: 5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.94 (1H, d, J 9.0 Hz, 2H of OC₆H₄CN or CH₂C₆H₄CN), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.26 (2H, d, J 8.5 Hz, 2H of OC₆H₄CN or CH₂C₆H₄CN), 6.96 (2H, d, J 9.0 Hz, 2H of OC₆H₄CN or CH₂C₆H₄CN), 6.86 (2H, d, J 8.5 Hz, 2H of OC₆H₄CN or CH₂C₆H₄CN), 4.65 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.88 (3H, s, OCH₃), 3.80 (1H, m, 1H of PhOpipH-2, H-6), 3.53 (3H, m, 1H of PhOpipH-2, H-6, CH ₂C₆H₄OCH₃), 3.24-3.11 (2H, m, 2H of PhOpipH-2, H-6), 2.91 (2H, m, 2H of pipH-2, H-6), 2.25 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.89-1.76 (4H, m, 4H of PhOpipH-3, H-5), 1.70 (2H, m, 2H of pipH-3, H-5); m/z: 572 [M+H]⁺.

Compound 164: tert-butyl 3-(2-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)pyridin-3-yl)prop-2-ynylcarbamate

To a solution of 5-chloro-6-(ethoxycarbonyl)nicotinic acid (0.201 g, 0.875 mmol, 1.0 eq) and 4-fluorobenzylpiperazine (0.204 g, 1.051 mmol, 1.2 eq) in dimethylformamide (4.0 mL) was added triethylamine (0.146 mL, 1.051 mmol, 1.2 eq) followed by HATU (0.366 g, 0.963 mmol, 1.1 eq). The reaction was shaken at room temperature for 3 hours before partitioning between EtOAc (80 mL) and water-NaHCO₃ (2:1, 60 mL). The organics were further washed with brine (80 mL), water (80 mL) and brine (80 mL) before drying (Na₂SO₄) and concentrating under reduced pressure. MPLC (30-95% EtOAc-hexane, 2-25 min) yielded ethyl 3-chloro-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate as a white solid (0.265 g, 75%); ¹H nmr (D₆-DMSO) 8.54 (1H, d, J 1.5 Hz, pyH-2 or pyH-4), 7.83 (1H, d, J 1.0 Hz, pyH-2 or pyH-4), 7.26 (2H, m, 2H of C₆H₄F), 6.99 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 4.48 (2H, q, J 7.0 Hz, OCH ₂CH₃), 3.55 (4H, m, 4H of piz), 2.45 (4H, m, 4H of piz), 1.43 (3H, t, J 7.0 Hz, OCH₂CH ₃); m/z 406, 408 [M+H]⁺. A solution of the ethyl 3-chloro-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate (0.265 g, 0.654 mmol, 1.0 eq) and N-Boc-propargylamine (0.122 g, 0.785 mmol, 1.2 eq) in dimethylformamide (7.0 mL) was degassed by bubbling argon through it. Triethylamine (0.14 mL, 0.981 mmol, 1.5 eq) was added followed by copper (I) iodide (0.006 g, 0.033 mmol, 0.05 eq) and tetrakis(triphenylphosphine)palladium (0.038 g, 0.033 mmol, 0.05 eq). The reaction mixture was further degassed before heating to 90° C. for 14 hours. The reaction was cooled and filtered through Celite®, eluting with EtOAc (80 mL). The filtrate was washed with water (100 mL), brine (80 mL), water (100 mL) and brine (80 mL). The organics were dried (Na₂SO₄) and concentrated under reduced pressure. Column chromatography (silica, 70% EtOAc-hexane) yielded the ethyl 3-chloro-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate starting material and ethyl 3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate as a colourless oil; ¹H nmr (CDCl₃) 8.60 (1H, d, J 2.0 Hz, pyH-2 or pyH-4), 7.87 (1H, d, J 2.0 Hz, pyH-2 or pyH-4), 7.26 (2H, m, 2H of C₆H₄F), 6.99 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 4.87 (1H, br s, NH), 4.47 (2H, q, J 7.0 Hz, OCH ₂CH₃), 4.21 (2H, d, J 5.5 Hz, CH ₂NHBoc), 3.77 (2H, m, 2H of piz), 3.37 (2H, m, 2H of piz), 2.51 (2H, m, 2H of piz), 2.38 (2H, m, 2H of piz), 1.47 (9H, s, C(CH₃)₃), 1.43 (3H, t, J 7.0 Hz, OCH₂CH ₃); m/z 525 [M+H]⁺. A solution of lithium hydroxide monohydrate (0.010 g, 0.229 mmol, 2.0 eq) in water (0.5 mL) was added to a solution of the ethyl 3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate (0.060 g, 0.115 mmol, 1.0 eq) in tetrahydrofuran-methanol (2:1, 1.5 mL). The reaction was stirred at room temperature for 40 minutes before neutralizing with HCl (approximately 0.2 mL of a 2M solution). The reaction mixture was concentrated to dryness to provide 3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinic acid, which was used without purification; m/z 497 [M+H]⁺. To a solution of the crude 3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinic acid (0.115 mmol, 1.0 eq) in dimethylformamide (2.0 mL) was added 1-(4-cyanobenzyl)-4-aminopiperidine dihydrochloride (0.040 g, 0.138 mmol, 1.2 eq) and HATU (0.052 g, 0.138 mmol, 1.2 eq). Triethylamine (0.056 mL, 0.403 mmol, 3.5 eq) was added and the reaction mixture was stirred at room temperature for 2.5 hours before partitioning between EtOAc (100 mL) and water (100 mL). The organics were further washed with brine (80 mL), water (80 mL) and brine (80 mL), dried (Na₂SO₄) and concentrated under reduced pressure. Column chromatography (silica, 3→6% MeOH—CH₂Cl₂) yielded Compound 164 as a yellow foam; ¹H nmr (CDCl₃) δ 8.46 (1H, d, J 2.0 Hz, pyH-4 or pyH-6), 7.85 (1H, d, J 2.0 Hz, pyH-4 or pyH-6), 7.80 (1H, d, J 8.0 Hz, CONH), 7.60 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.29-7.25 (2H, m, 2H of C₆H₄F), 7.00 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 4.88 (1H, m, NHCO₂C), 4.23 (2H, d, J 5.5 Hz, CCH₂NH), 3.99 (1H, m, pipH-4), 3.80-3.40 (4H, br m, 4H of piz), 3.56 (2H, s. CH ₂C₆H₄CN or CH ₂C₆H₄F), 3.51 (2H, s, CH ₂C₆H₄CN or CH ₂C₆H₄F), 2.80 (2H, m, 2H of pip), 2.46 (4H, m, 4H of piz), 2.23 (2H, t, J 11.0 Hz, 2H of pip), 2.01 (2H, m, 2H of pip), 1.63 (2H, m, 2H of pip), 1.46 (9H, s, C(CH₃)₃); m/z: 694 [M+H]⁺.

Compound 165: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-cyanophenoxy)piperidin-1-yl)picolinamide

To a solution of 5-bromopicolinic acid (0.50 g, 2.48 mmol, 1.0 eq) and 1-(4-cyanobenzyl)-4-aminopiperidine dihydrochloride (0.71 g, 2.48 mmol, 1.0 eq) in dimethylformamide (10 mL) was added triethylamine (1.21 mL, 8.66 mmol, 3.5 eq) and HATU (1.13 g, 2.97 mmol, 1.2 eq). The reaction mixture was stirred at room temperature 14 hours before partitioning between EtOAc (120 mL) and water (100 mL). The organics were washed with brine (100 mL), water (100 mL) and brine (100 mL), dried (Na₂SO₄) and concentrated under reduced pressure. MPLC (0%, 5%, 10% MeOH—CH₂Cl₂, 0→5→25→35 min) yielded 5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide as a waxy brown solid: ¹H nmr (CDCl₃) 8.60 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, d, J 8.5 Hz, pyH-3), 7.97 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (1H, d, J 7.5 Hz, NH), 7.63 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.50 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 4.00 (1H, m, pipH-4), 3.63 (2H, s, CH ₂C₆H₄CN), 2.88 (2H, m, 2H of pip), 2.30 (2H, m, 2H of pip), 2.04 (2H, m, 2H of pip), 1.70 (2H, m, 2H of pip); m/z 399, 401 [M+H]⁺. To a mixture of the 5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide (0.040 g, 0.100 mmol, 1.0 eq) 4-(4-piperidinyloxy)benzonitrile (0.024 g, 0.120 mmol, 1.2 eq), sodium t-butoxide (0.019 g, 0.201 mmol, 2.0 eq) and S-Phos (0.004 g, 0.010 mmol, 0.1 eq) was added toluene (1.0 mL). The resulting mixture was degassed by bubbling argon through the mixture.

Tris(dibenzylideneacetone)dipalladium (0.005 g, 0.005 mmol, 0.05 eq) was added and the mixture further degassed before sealing the reaction and heating to 105° C. for 14 hours. The reaction was filtered through celite, eluting with 5% MeOH—CH₂Cl₂ (3×15 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by RP-HPLC to yield Compound 165: ¹H nmr (CDCl₃) δ 8.19 (1H, d, J 3.0 Hz, pyH-6), 8.04 (1H, d, J 9.0 Hz, pyH-3), 7.72 (1H, d, J 8.5 Hz, NH), 7.60 (4H, m, 2H of OC₆H₄CN, 2H of CH₂C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of CH₂C₆H₄CN), 7.24 (1H, dd, J 8.0, 3.0 Hz, pyH-4), 6.97 (2H, d, J 9.0 Hz, 2H of OC₆H₄CN), 4.64 (1H, m, PhOpipH-4), 3.98 (1H, m, pipH-4), 3.63-3.57 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH ₂C₆H₄CN), 3.38-3.30 (2H, m, 2H of PhOpipH-2, H-6), 2.80 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.16-2.05 (2H, m, 2H of PhOpipH-3, H-5), 2.01-1.92 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); m/z: 522 [M+H]⁺.

Compound 166: N2-(1-(4-cyanobenzyl)piperidin-4-yl)-N5-(1-(4-cyanophenyl)piperidin-4-yl)pyridine-2,5-dicarboxamide

¹H nmr (CDCl₃) δ 8.92 (1H, d, J 1.0 Hz, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3), 8.16 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (1H, d, J 8.5 Hz, BnpipNH), 7.61 (2H, d, J 8.5 Hz, 2H of CH₂C₆H₄CN), 7.47 (4H, m, 2H of CH₂C₆H₄CN, 2H of NC₆H₄CN), 6.88 (2H, d, J 9.0 Hz, 2H of NC₆H₄CN), 6.21 (1H, d, J 7.5 Hz, PhpipNH), 4.26 (1H, m, PhpipH-4), 3.99 (1H, m, BnpipH-4), 3.89 (2H, m, 2H of PhpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.08 (2H, t, J 11.5 Hz, 2H of PhpipH-2, H-6), 2.81 (2H, m, 2H of BnpipH-2, H-6), 2.26-2.16 (4H, m, 2H of PhpipH-3, H-5, 2H of BnpipH-2, H-6), 2.02 (2H, m, 2H of BnpipH-3, H-5), 1.70-1.59 (4H, m, 2H of PhpipH-3, H-5, 2H of BnpipH-3, H-5); m/z: 548 [M+H]⁺.

Compound 167: N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.61 (1H, dd, J 2.0, 1.0 Hz, pyH-6), 8.25 (1H, dd, J 8.0, 1.0 Hz, pyH-3), 7.99 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.58 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.01-6.94 (4H, m, 2H of C₆H₄CN, 2H of C₆H₄F), 6.89-6.84 (2H, m, 2H of C₆H₄F), 4.60 (1H, br s, cHexH-1 or PhOpipH-4), 4.52 (1H, m, cHexH-1 or PhOpipH-4), 4.10 (1H, m, cHexH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.36 (1H, m, 1H of PhOpipH-2, H-6), 2.11-1.90 (12H, m, cHexH-2, H-3, H-5, H-6, PhOpipH-3, H-5); m/z: 543 [M+H]⁺.

Compound 265: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-cyanophenoxy)piperidin-1-yl)picolinamide

¹H nmr (CDCl₃) δ 8.13 (1H, d, J 3.0 Hz, pyH-6), 8.01 (1H, d, J 9.0 Hz, pyH-3), 7.70 (1H, d, J 8.5 Hz, NH), 7.62-7.57 (4H, 4×ArH), 7.45 (2H, d, J 8.0 Hz, 2H of CH₂C₆H₄CN or OC₆H₄CN), 7.19 (1H, dd, J 9.0, 3.0 Hz, pyH-4), 6.94 (2H, d, J 9.0 Hz, 2H of CH₂C₆H₄CN or OC₆H₄CN), 4.54 (1H, m, PhOpipH-4), 3.98 (1H, m, pipH-4), 3.75 (1H, dd, J 12.5, 3.0 Hz, 1H of PhOpipH-2, H-6), 3.55 (2H, s, CH ₂C₆H₄CN), 3.49 (1H, m, 1H of PhOpipH-2, H-6), 3.31 (1H, dd, J 13.0, 7.5 Hz, 1H of PhOpipH-2, H-6), 3.23 (1H, m, 1H of PhOpipH-2, H-6), 2.80 (2H, m, 2H of pip), 2.22 (2H, dd, J 11.0, 10.0 Hz, 2H of pip), 2.14 (1H, m, 1H of PhOpip), 1.99 (3H, m, 2H of pip, 1H of PhOpip), 1.79 (2H, m, 2H of PhOpip), 1.62 (2H, m, 2H of pip); m/z: 521 [M+H]⁺.

Compound 266: 5-(4-(4-chlorobenzoyl)piperidin-1-yl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.18 (1H, br s, 1×py), 7.98 (1H, d, J 8.5 Hz, NH or 1×py), 7.98 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄Cl), 7.96 (1H, m, NH or 1×py), 7.90 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄Cl), 7.75 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄Cl), 7.47 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄Cl), 7.25 (1H, m, NH or 1×py), 4.26 (2H, s, CH ₂C₆H₄CN), 4.19 (1H, m, pipH-4 or BzpipH-4), 3.90 (2H, m, 2H of pip or Bzpip), 3.62 (2H, m, 2H of pip or Bzpip), 3.45 (1H, m, pipH-4 or BzpipH-4), 3.07 (2H, m, 2H of pip or Bzpip), 2.81 (2H, m, 2H of pip or Bzpip), 2.20-1.85 (8H, m, 4H of pip, 4H of Bzpip); m/z: 542, 544 [M+H]⁺.

Compound 267: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-cyanophenyl)piperidin-4-ylamino)picolinamide

¹H nmr (CDCl₃) δ 7.99 (1H, d, J 8.5 Hz, pyH-3), 7.89 (1H, d, J 2.0 Hz, pyH-6), 7.65 (1H, d, J 8.5 Hz, NH), 7.66 (2H, d, J 9.0 Hz, 2H of CH₂C₆H₄CN or NC₆H₄CN), 7.60 (2H, d, J 8.5 Hz, 2H of CH₂C₆H₄CN or NC₆H₄CN), 7.45 (2H, d, J 7.5 Hz, 2H of CH₂C₆H₄CN or NC₆H₄CN), 6.94 (1H, dd, J 9.0, 2.5 Hz, pyH-4), 6.89 (2H, d, J 9.0 Hz, 2H of CH₂C₆H₄CN or NC₆H₄CN), 3.99 (2H, m, 2H of pip), 3.85 (2H, m, 2H of pip), 3.60 (1H, m, 1H of pip), 3.55 (2H, s, CH ₂C₆H₄CN), 3.08 (2H, t, J 11.5 Hz, 2H of pip), 2.80 (2H, m, 2H of pip), 2.21 (4H, m, 4H of pip), 1.99 (2H, m, 2H of pip), 1.59 (3H, m, 3H of pip); m/z: 520 [M+H]⁺.

Compound 268: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(2-(4-fluorophenyl)propan-2-yl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.57 (1H, m, pyH-6), 8.20 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, d, J 8.5 Hz, NH), 7.84 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.49-7.29 (4H, m, 2H of C₆H₄CN, 2H of C₆H₄F), 6.98 (2H, t, J 9.0 Hz, 2H of C₆H₄F), 4.00 (1H, m, pipH-4), 3.76 (2H, m, 2H of piz), 3.56 (2H, s, CH ₂C₆H₄CN), 3.33 (2H, m, 2H of piz), 2.81 (2H, m, 2H of pip), 2.57 (2H, m, 2H of piz), 2.40 (2H, m, 2H of piz), 2.22 (2H, dd, J 11.0, 9.5 Hz, 2H of pip), 2.01 (2H, m, 2H of pip), 1.63 (2H, m, 2H of pip), 1.33 (6H, s, C(CH₃)₂); m/z: 569 [M+H]⁺.

Compound 269: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(pyridin-4-yloxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.44 (2H, d, J 6.0 Hz, 2H of Opy), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, m, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.60 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.81 (2H, d, J 6.5 Hz, 2H of Opy), 4.72 (1H, m, PyOpipH-4), 4.05-3.87 (3H, m, pipH-4, 2H of PyOpipH-2, H-6), 3.63 (1H, m, 1H of PyOpipH-2, H-6), 3.56 (2H, s, CH₂C₆H₄CN), 3.41 (1H, m, 1H of PyOpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 10.0, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 2.00-1.79 (4H, m, 4H of PyOpipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m/z: 525 [M+H]⁺.

Compound 270: (S)—N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorophenoxy)pyrrolidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃ @50° C.) δ 8.72 (1H, br s, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3), 7.98 (1H, m, NH or pyH-4), 7.90 (1H, d, J 8.0 Hz, NH or pyH-4), 7.59 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.97 (2H, m, 2H of C₆H₄F), 6.80 (2H, m, 2H of C₆H₄F), 4.90 (1H, m, pyrrolidineH-3), 4.01 (1H, m, pipH-4), 3.98-3.86 (2H, m, 1H of pyrrolidineH-2, 1H of pyrrolidineH-5), 3.80-3.50 (2H, m, 1H of pyrrolidineH-2, 1H of pyrrolidineH-5), 3.56 (2H, s, CH ₂C₆H₄CN), 2.80 (2H, m, 2H of pipH-2, H-6), 2.29-2.14 (4H, m, 2H of pipH-2, H-6, pyrrolidineH-4), 2.02 (2H, m, 2H of pipH-3, H-5), 1.66 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃ @50° C.) δ −122.3; m/z: 528 [M+H]⁺.

Compound 271: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.58 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.94-7.84 (3H, m, NH, pyH-4, 1H of BzH-5 or BzH-6), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.99 (1H, m, BzH-5 or BzH-6), 6.89 (ddd, J 11.0, 8.5, 2.5 Hz, BzH-3), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH-4), 3.75 (1H, m, 1H of BzpipH-2, H-6), 3.56 (2H, s, CH₂C₆H₄CN), 3.41 (1H, m, BzpipH-4), 3.20 (1H, m, 1H of BzpipH-2, H-6), 3.07 (1H, m, 1H of BzpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, d, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.03 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.86 (1H, m, 1H of BzpipH-3, H-5), 1.75-1.58 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5); m/z: 572 [M+H]⁺.

Compound 272: 5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 9.91 (1H, s, 1×NH or ArH), 8.68 (1H, m, 1×NH or ArH), 8.42-8.33 (3H, m, NH, 2×ArH or 3×ArH), 8.01-7.95 (3H, m, NH, 2×ArH or 3×ArH), 7.20-7.08 (5H, m, NH, 4×ArH or 5×ArH), 6.97 (2H, d, J 9.0 Hz, 2×ArH), 4.67 (1H, m, 1H of BzpipH-2, H-4, H-6), 3.76 (1H, m, 1H of BzpipH-2, H-4, H-6), 3.49 (1H, m, 1H of BzpipH-2, H-4, H-6), 3.26 (1H, m, 1H of BzpipH-2, H-4, H-6), 3.14 (1H, m, 1H of BzpipH-2, H-4, H-6), 2.04 (1H, m, 1H of BzpipH-3, H-5), 1.84 (3H, m, 3H of BzpipH-3, H-5); m/z: 543 [M+H]⁺.

Compound 273: 5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 9.90 (1H, s, NH or 1×ArH), 8.68 (1H, m, 1×ArH), 8.41-8.33 (3H, NH, 2×ArH or 3×ArH), 7.96 (1H, dd, J 8.0, 2.0 Hz, 1×ArH), 7.11-7.08 (4H, m, NH, 3×ArH or 4×ArH), 7.02-6.95 (3H, NH, 2×ArH or 3×ArH), 6.89-6.85 (2H, m, 2×ArH), 4.54 (1H, m, PhOpipH-4), 3.91 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 1H of PhOpipH-2, H-6), 3.39 (1H, m, 1H of BzpipH-2, H-6), 2.00 (2H, m, 2H of PhOpipH-3, H-5), 1.86 (2H, m, 2H of PhOpipH-3, H-5); m/z: 531 [M+H]⁺.

Compound 274: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-methoxyphenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, s, pyH-6), 8.23 and 8.11 (1H, 2m, pyH-3), 7.87 (2H, m, NH, pyH-4), 7.61 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.92-6.73 (4H, m, 4H of C₆H₄OCH₃), 4.24 (2H, m, 1H of PhOpipH-2, H-6, PhOpipH-3), 3.99 (1H, m, pipH-4), 3.75 (3H, s, OCH₃), 3.67 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.43 (1H, m, 1H of PhOpipH-2, H-6), 3.29 (1H, m, 1H of PhOpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.01 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-4, H-5), 1.82 (1H, m, 1H of PhOpipH-4, H-5), 1.65 (3H, m, 2H of pipH-3, H-5, 1H of PhOpipH-4, H-5); m/z: 555 [M+H]⁺.

Compound 275: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-methoxyphenyl)piperidin-4-ylamino)picolinamide

¹H nmr (CDCl₃) δ 7.98 (1H, d, J 8.5 Hz, pyH-3), 7.88 (1H, d, J 2.0 Hz, pyH-6), 7.68 (1H, d, J 8.5 Hz, NH), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.47 (2H, d, J 7.5 Hz, 2H of C₆H₄CN), 6.93 (3H, m, 2H of C₆H₄OCH₃, pyH-4), 6.84 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.03-3.97 (2H, m, 2×pipH-4), 3.77 (3H, s, OCH₃), 3.58 (2H, s, CH ₂C₆H₄CN), 3.49 (4H, m, 2×2H of pipH-2, H-6), 2.83 (4H, m, 2×2H of pipH-2, H-6), 2.28-2.15 (4H, m, 2×2H of pipH-3, H-5), 2.00 (2H, m, 2H of pipH-3, H-5), 1.66 (2H, m, 2H of pipH-3, H-5); m/z: 525 [M+H]⁺.

Compound 276: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-fluorophenyl)piperidin-4-ylamino)picolinamide

¹H nmr (CDCl₃) δ 8.17 (1H, d, J 3.0 Hz, pyH-6), 8.02 (1H, d, J 8.5 Hz, pyH-3), 7.73 (1H, d, J 8.5 Hz, CONH), 7.61 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₄H₄CN), 7.22 (1H, dd, J 9.0, 3.0 Hz, pyH-4), 6.89 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.56 (2H, dd, J 9.0, 4.5 Hz, 2H of C₆H₄F), 3.98 (1H, m, pipH-4), 3.79 (2H, m, 2H of Phpip), 3.55 (2H, s, CH ₂C₆H₄CN), 3.44 (1H, m, PhpipH-4), 3.04 (2H, m, 2H of Phpip), 2.80 (2H, m, 2H of pipH-2, H-6), 2.21 (4H, m, 2H of Phpip, 2H of pipH-2, H-6), 1.99 (2H, m, 2H of pipH-3, H-5), 1.76-1.47 (4H, m 2H of pipH-3, H-5, 2H of Phpip); m/z: 513 [M+H]⁺.

Compound 277: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(3-methoxyphenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃ @50° C.) δ 8.58 (1H, s, pyH-6), 8.12 (1H, br s, pyH-3), 7.87 (1H, d, J 8.5 Hz, NH), 7.83 (1H, m, pyH-4), 7.60 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.12 (1H, t, J 7.5 Hz, 1H of C₆ H ₄OCH₃), 6.49 (1H, d, J 8.5 Hz, 1H of C₆ H ₄OCH₃), 6.40 (2H, m, 2H of C₆ H ₄OCH₃), 4.32 (1H, m, PhOpipH-3), 4.00 (1H, m, pipH-4), 3.76 (3H, s, OCH₃), 3.59 (1H, m, 1H of PhOpipH-2), 3.56 (2H, s, CH ₂C₆H₄CN), 3.37 (2H, m, PhOpipH-6), 2.80 (3H, m, 2H of pipH-2, H-6, 1H of PhOpipH-2), 2.25 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 1.98 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-4, H-5), 1.71-1.59 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-4, H-5); m/z: 554 [M+H]⁺.

Compound 278: (R)—N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorophenoxy)pyrrolidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃ @50° C.) δ 8.72 (1H, br s, pyH-6), 8.22 (1H, d, J 7.5 Hz, pyH-3 or H-4), 7.98 (1H, br s, NH), 7.90 (1H, d, J 8.0 Hz, pyH-3 or H-4), 7.59 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.98 (2H, m, 2H of C₆H₄F), 6.90-6.78 (2H, m, 2H of C₄H₄F), 4.92 (1H, m, pyrrolidineH-3), 4.01 (1H, m, pipH-4), 3.98-3.85 (2H, m, 1H of pyrrolidineH-2, 1H of pyrrolidineH-5), 3.78-3.50 (2H, m, 1H of pyrrolidineH-2, 1H of pyrrolidineH-5), 3.56 (2H, s, CH₂C₆H₄CN), 2.80 (2H, m, 2H of pipH-2, H-6), 2.25 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.16 (2H, m, pyrrolidineH-4), 2.02 (2H, m, 2H of pipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 528 [M+H]⁺.

Compound 279: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-((trans)-4-(4-cyanophenoxy)-3-fluoropiperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.62 (1H, m, pyH-6), 8.26 (1H, d, J 8.0 Hz, pyH-3), 7.92 (2H, m, NH, pyH-4), 7.63 (2H, d, J 9.0 Hz, 2H of OC₆H₄CN), 7.61 (2H, d, J 8.0 Hz, 2H of CH₂C₆ H ₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of CH₂C₆ H ₄CN), 7.01 (2H, d, J 9.0 Hz, 2H of OC₆H₄CN), 4.75 (1H, m, PhOpipH-4), 4.75-4.03 (2H, m, 2H of PhOpipH-2, H-3, H-6), 4.01 (1H, m, pipH-4), 3.78 (1H, m, 1H of PhOpipH-2, H-3, H-6), 3.68-3.37 (2H, m, 2H of PhOpipH-2, H-3, H-6), 3.57 (2H, s, CH ₂C₆H₄CN), 2.82 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.63 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-6); m/z: 567 [M+H]⁺.

Compound 280: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-((1R,3r,5S)-3-(4-cyanophenoxy)-8-azabicyclo[3.2.1]octane-8-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.69 (1H, d, J 1.5 Hz, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.97 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.92 (1H, d, J 8.5 Hz, NH), 7.61 (2H, d, J 8.5 Hz, 2H of CH₂C₆ H ₄CN), 7.57 (2H, d, J 9.0 Hz, 2H of OC₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of CH₂C₆ H ₄CN), 6.93 (2H, d, J 9.0 Hz, 2H of OC₆H₄CN), 4.67 (1H, m, 1H of PhOpipH-2, H-4, H-6), 4.82 (1H, m, 1H of PhOpipH-2, H-4, H-6), 4.13 (1H, m 1H of PhOpipH-2, H-4, H-6), 4.01 (1H, m pipH-4), 3.56 (2H, s, CH ₂C₆H₄CN), 2.81 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.5 Hz, pipH-2, H-6), 2.17 (4H, m, 4H of PhOpip), 2.01 (2H, m, 2H of pipH-3, H-5), 1.86 (2H, d, J 7.5 Hz, 2H of PhOpip), 1.68 (4H, m, 2H of pipH-3, H-5, 2H of PhOpip); m/z: 575 [M+H]⁺.

Compound 281: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3,4-difluorobenzoyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.94-7.84 (3H, NH, pyH-4, BzH-5 or H-6), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.99 (1H, m, BzH-5 or H-6), 6.89 (1H, ddd, J 11.0, 9.0, 2.0 Hz, BzH-2), 4.63 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.71 (1H, m, 1H of BzpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.41 (1H, m, BzpipH-4), 3.20 (1H, m 1H of BzpipH-2, H-6), 3.08 (1H, m, BzpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, 11.5, 10.0 Hz, pipH-2, H-6), 2.12-1.82 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.78-1.59 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5); m/z: 572 [M+H]⁺.

Compound 282: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(2,4-difluorophenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 9.0 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.98 (1H, td, J 9.0, 5.5 Hz, PhH-5), 6.87 (1H, ddd, J 11.0, 8.5, 3.0 Hz, PhH-2), 6.80 (1H, m, PhH-6), 4.47 (1H, m, PhOpipH-4), 4.00 (1H, m, pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.68 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.49 (1H, m, 1H of PhOpipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.03-1.96 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.85 (2H, m, 2H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 560 [M+H]⁺.

Compound 283: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(pyridin-3-yloxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.61 (1H, m, pyH-6), 8.33 (1H, m, OpyH-2), 8.26-8.23 (2H, m, pyH-3, 1H of OpyH), 7.92 (1H, d, J 9.5 Hz, NH), 7.89 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.23 (2H, m, 2H of OpyH), 4.66 (1H, m pyOpipH-4), 4.01 (1H, m, pipH-4), 3.91 (2H, m, 2H of pyOpipH-2, H-6), 3.66 (1H, m, 1H of pyOpipH-2, H-6), 3.40 (1H in, m, H of pyOpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.04-1.88 (6H, m, 2H of pipH-3, H-5, 4H of pyOpipH-3, H-5), 3.56 (2H, s. CH₂C₆H₄CN), 1.64 (2H, m, 2H of pipH-3, H-5); m/z: 525 [M+H]⁺.

Compound 284: ethyl 4-(1-(6-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)nicotinoyl)piperidin-4-yloxy)benzoate

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.99 (2H, d, J 8.5 Hz, 2H of C₆H₄CO₂Et), 7.92 (1H, d, J 9.5 Hz, NH), 7.89 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.92 (2H, d, J 9.0 Hz, 2H of C₆H₄CO₂Et), 4.72 (1H, m, PhOpipH-4), 4.34 (2H, q, J 7.0 Hz, OCH_(—)2CH₃), 4.02-3.87 (3H, m, pipH-4, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH ₂C₆H₄CN), 3.55 (1H, m, 1H of PhOpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, t, J 10.5 Hz, pipH-2, H-6), 2.03-1.88 (6H, m, pipH-3, H-5, 4H of PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5), 1.37 (3H, t, J 7.0 Hz, OCH₂CH ₃); m/z: 597 [M+H]⁺.

Compound 285: 5-(4-(4-cyanobenzyl)piperazine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.58 (1H, m, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3), 7.90 (1H, d, J 9.0 Hz, NH), 7.86 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.62 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.25 (2H, d, J 8.0 Hz, 2H of C₆H₄OCH₃), 6.86 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 4.00 (1H, m, pipH-4), 3.80 (5H, m, 2H of piz, OCH₃), 3.59 (2H, s, 1×CH₂Ar), 3.52 (2H, s, 1×CH₂Ar), 3.41 (2H, m, 2H of piz), 2.90 (2H, m, 2H of pipH-2, H-6), 2.54 (2H, m, 2H of piz), 2.41 (2H, m, 2H of piz), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.01 (2H, m, 2H of pipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m/z: 553 [M+H]⁺.

Compound 286: 5-(4-(4-cyano-2-methoxyphenoxy)piperidin-1-yl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.18 (1H, d, J 2.5 Hz, pyH-6), 8.02 (1H, d, J 9.0 Hz, pyH-3), 7.73 (1H, d, 8.5 Hz, CONH), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.26-7.21 (2H, m, pyH-4, C₆H₃(OCH₃)CNH-5), 7.11 (1H, d, J 1.5 Hz, C₆H₃(OCH₃)CNH-3), 6.95 (1H, d, J 8.5 Hz, C₆H₃(OCH₃)CNH-6), 4.60 (1H, m, PhOpipH-4), 3.99 (1H, m, pipH-4), 3.86 (3H, s, OCH₃), 3.69-3.61 (4H, m, 2H of PhOpipH-2, H-6, CH ₂C₆H₄CN), 3.30 (2H, m, 2H of PhOpipH-2, H-6), 2.84 (2H, m, 2H of pipH-2, H-6), 2.26 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.14-1.96 (6H, m, 2H of pipH-3, H-5, 4H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 552 [M+H]⁺.

Compound 287: N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, d, J 2.0 Hz, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.92 (1H, m, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.88 (2H, d, J 6.0 Hz, C₆H₃F₂H-2, H-6), 6.68 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4), 4.67 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.87 (3H, s, OCH₃), 3.77 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, BzpipH-4), 3.49 (2H, s, CH ₂C₆H₃F₂), 3.17 (2H, m, 2H of BzpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.83 (3H, m, 3H of BzpipH-3, H-5), 1.66 (2H, m, 2H of pipH-3, H-5); m/z: 577 [M+H]⁺.

Compound 288: N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.54 (1H, m, pyH-6), 8.17 (1H, d, J 8.0 Hz, pyH-3), 7.91 (2H, dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.87 (1H, m, NH), 7.82 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.10 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.82 (2H, d, J 6.5 Hz, C₆H₃F₂H-2 and H-6), 6.62 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4), 4.60 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH-4), 3.69 (1H, m, 1H of BzpipH-2, H-6), 3.47 (1H, m, BzpipH-4), 3.44 (2H, s, CH₂C₆H₃F₂), 3.11 (2H, m, 2H of BzpipH-2, H-6), 2.78 (2H, m, 2H of pipH-2, H-6), 2.17 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 1.95 (2H, m, 2H of pipH-3, H-5), 1.76 (4H, m, 4H of BzpipH-3, H-5), 1.60 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −104.4, −110.5; m/z: 565 [M+H]⁺.

Compound 289: 5-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.91 (1H, d, J 8.0 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.59 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 9.69 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.87 (2H, d, J 8.0 Hz, C₆H₃F₂H-2, H-6), 6.68 (1H, m, C₆H₃F₂H-4), 4.70 (1H, m, PhOpipH-4), 4.00 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH ₂C₆H₃F₂), 3.41 (1H, m, 1H of PhOpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.03-1.1.83 (6H, m, 2H of pipH-3, H-5, 4H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −110.5; m/z: 560 [M+H]⁺.

Compound 290: tert-butyl 3-(2-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)pyridin-3-yl)propylcarbamate

¹H nmr (CDCl₃) δ 8.42 (1H, d, J 1.5 Hz, pyH-6), 8.03 (1H, d, J 8.5 Hz, PyCONH), 7.61 (3H, m, pyH-4, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.27 (2H, dd, J 8.6, 6.0 Hz, 2H of C₆H₄F), 7.01 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 5.02 (1H, m, NHCO₂), 3.93 (1H, m, pipH-4), 3.79 (2H, m, 2H of piz), 3.56 (2H, s, CH ₂C₆H₄CN or CH ₂C₆H₄F), 3.50 (2H, s, CH ₂C₆H₄CN or CH ₂C₆H₄F), 3.40 (2H, m, 2H of piz), 3.17 (4H, m, PyCH ₂CH₂CH ₂NH), 2.81 (2H, m, 2H of pipH-2, H-6), 2.79 (2H, m, 2H of piz), 2.53 (2H, m, 2H of piz), 2.21 (2H, t, J 10.5 Hz, 2H of pipH-2, H-6), 2.00 (2H, m, 2H of pipH-3, H-5), 1.84 (2H, m, PyCH₂CH ₂CH₂NH), 1.66 (2H, m, 2H of pipH-3, H-5), 1.43 (9H, s, C(CH₃)₃); m/z: 699 [M+H]⁺.

Compound 291: N-(1-(4-cyanobenzyl)piperidin-4-yl)-3-(5,21-dioxo-25-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-8,11,14,17-tetraoxa-4,20-diazapentacosyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide (as its trifluoroacetate salt)

m/z: 1072 [M+H]⁺.

Compound 292: N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-((S)-3-(4-fluorophenoxy)pyrrolidine-1-carbonyl)picolinamide

m/z: 539 [M+H]⁺ (found [M+H]⁺, 539.2314, C₂₉H₂₉F₃N₄O₃ requires [M+H]⁺ 539.2265).

Compound 293: N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(p-tolyloxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.09 (2H, d, J 9.0 Hz, 2H of C₆H₄CH₃), 6.88 (2H, d, J 6.5 Hz, C₆H₃F₂H-2, H-6), 6.82 (2H, d, J 8.5 Hz, 2H of C₆H₄CH₃), 6.80 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4), 4.56 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH ₂C₆H₃F₂), 2.83 (2H, m, 2H of pipH-2, H-6), 2.29 (3H, s, ArCH3), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.04-1.84 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.68 (2H, m, 2H of pipH-3, H-5); m/z: 550 [M+H]⁺.

Compound 294: N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.61 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, m, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.55 (2H, d, J 8.5 Hz, 2H of C₆H₄CF₃), 6.98 (2H, d, J 8.5 Hz, 2H of C₆H₄CF₃), 6.88 (2H, d, J 6.0 Hz, C₆H₃F₂H-2, H-6), 6.68 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4), 4.70 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.87 (2H, m, 2H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH ₂C₆H₃F₂), 3.35 (1H, m, 1H of PhOpipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.12-1.84 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 603 [M+H]⁺.

Compound 295: N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.28 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, m, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.98 (2H, t, J 8.0 Hz, 2H of C₆H₄F), 6.89-6.84 (4H, m, 2H of C₆H₄F, C₆H₃F₂H-2, H-6), 6.68 (1H, br t, J 8.5 Hz, C₆H₃F₂H-4), 4.52 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH ₂C₆H₃F₂), 3.36 (1H, m, 1H of PhOpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.04-1.85 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m/z: 525 [M+H]⁺.

Compound 296: N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-methoxyphenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, d, J 8.0 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.90-6.82 (6H, m, C₆H₄OCH₃, C₆H₃F₂H-2, H-6), 6.69 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4), 4.47 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.77 (3H, s, OCH₃), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.50 (2H, s, CH ₂C₆H₃F₂), 3.35 (1H, m, 1H of PhOpipH-2, H-6), 2.84 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.04-1.83 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.66 (2H, m, 2H of pipH-3, H-5); m/z: 565 [M+H]⁺ (found [M+H]⁺, 565.2657, C₃₁H₃₄F₂N₄O₄ requires [M+H]⁺ 565.2621).

Compound 297: N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(3,4-difluorophenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.94 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.07 (1H, q, J 9.5 Hz, 1H of COC₆H₃F₂), 6.91 (2H, d, J 6.0 Hz, C₆H₃F₂H-2, H-6), 6.78-6.17 (2H, m, 2H of COC₆H₃F₂), 6.62 (1H, m, C₆H₃F₂H-4), 4.51 (1H, m, PhOpipH-4), 4.04 (1H, m, pipH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.61 (3H, m, CH ₂C₆H₃F₂, 1H of PhOpipH-2, H-6), 3.37 (1H, m, 1H of PhOpipH-2, H-6), 2.95 (2H, m, 2H of pipH-2, H-6), 2.33 (2H, m, 2H of pipH-2, H-6), 2.08-1.76 (8H, m, pipH-3, H-5, PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −75.8, −134.9, −146.9; m/z: 571 [M+H]⁺ (found [M+H]⁺, 571.2402, C₃₀H₃₀F₄N₄O₃ requires [M+H]⁺ 571.2327).

Compound 298: 5-(4-(3,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.96 (1H, d, J 8.5 Hz, NH), 7.93-7.85 (2H, m, pyH-4, COC₆H₃F₂H-5 or H-6), 6.99 (1H, td, J 7.5, 2.0 Hz, COC₆H₃F₂H-5 or H-6), 6.91-6.85 (3H, m, COC₆H₃F₂H-2, CH₂C₆H₃F₂H-2, H-6), 6.72 (1H, br t, J 9.0 Hz, CH₂C₆H₃F₂H-4), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.04 (1H, m, pipH-4), 3.70 (1H, m, 1H of BzpipH-2, H-6), 3.61 (2H, s. CH ₂C₆H₃F₂), 3.41 (1H, m, BzpipH-4), 3.21 (1H, m, BzpipH-2, H-6), 3.07 (1H, m, BzpipH-2, H-6), 2.95 (2H, m, 2H of pipH-2, H-6), 2.33 (2H, m, 2H of pipH-2, H-6), 2.04 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.88 (1H, m, 1H of BzpipH-3, H-5), 1.74 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −75.8, −101.2, −106.5; m/z: 583 [M+H]⁺ (found [M+H]⁺, 583.2365, C₃₂H₃₄F₂N₄O₄ requires [M+H]⁺ 583.2327).

Compound 299: N-((cis)-4-(3,5-difluorophenoxy)cyclohexyl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.25 (1H, d, J 8.5 Hz, pyH-3), 8.00 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.98 (2H, dd, J 9.0, 8.0 Hz, 2H of C₆H₄F), 6.86 (2H, dd, J 9.5, 4.5 Hz, 2H of C₆H₄F), 6.45-6.35 (3H, m, C₆H₃F₂), 4.52 (1H, m, 1H of cyHexH-1 or cyHexH-4 or PhOpipH-4), 4.46 (1H, m, 1H of cyHexH-1 or cyHexH-4 or PhOpipH-4), 4.09 (1H, m, 1H of cyHexH-1 or cyHexH-4 or PhOpipH-4), 3.89 (2H, m 2H of PhOpipH-2, H-6), 3.64 (1H, m, PhOpipH-2, H-6), 3.36 (1H, m, PhOpipH-2, H-6), 2.08-1.75 (12H, m, cyHexH-2, H-3, H-5, H-6 and PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −109.4, −122.5; n/z: 525 [M+H]⁺.

Compound 300: N-((cis)-4-(3,5-difluorophenoxy)cyclohexyl)-5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.5 Hz, pyH-3), 8.00 (1H, d, J 8.5 Hz, NH), 7.93 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.45-6.35 (3H, m, C₆H₃F₂), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.46 (1H, m, cyHexH-1 or H-4), 4.09 (1H, m, cyHexH-1 or H-4), 3.87 (3H, s, OCH₃), 3.77 (1H, m, 1H of BzpipH-2, H-6), 3.53 (1H, m, BzpipH-4), 3.16 (2H, m, 2H of BzpipH-2, H-6), 2.08-2.03 (3H, m, 3H of cyHexH-2, H-3, H-5, H-6 and BzpipH-3, H-5), 1.89-1.71 (9H, m, 9H of cyHexH-2, H-3, H-5, H-6 and BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −109.4; m/z: 578 [M+H]⁺.

Compound 301: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)picolinamide

¹H nmr (CDCl₃) δ 8.19 (1H, d, J 3.0 Hz, pyH-6), 8.01 (1H, d, J 8.5 Hz, pyH-3), 7.78 (1H, d, J 8.5 Hz, NH), 7.64 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.55 (2H, d, J 9.0 Hz, 2H of C₆H₄CF₃), 7.50 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.23 (1H, dd, J 9.0, 3.0 Hz, pyH-4), 6.98 (2H, d, J 9.0 Hz, 2H of C₆H₄CF₃), 4.62 (1H, heptet, J 3.0 Hz, PhOpipH-4), 4.04 (1H, m, pipH-4), 3.78 (2H, s, CH ₂C₆H₄CN), 3.59 (2H, ddd, J 12.5, 8.5, 4.0 Hz, 2H of PhOpipH-2, H-6), 3.34 (2H, ddd, J 12.5, 7.0, 3.5 Hz, 2H of PhOpipH-2, H-6), 3.00 (2H, m, 2H of pipH-2, H-6), 2.43 (2H, m, 2H of pipH-2, H-6), 2.14-1.92 (6H, m, PhOpipH-3, H-5, 2H of pipH-3, H-5), 1.77 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −61.6; m/z: 564 [M+H]⁺ (found [M+H]⁺, 564.2539, C₃₁H₃₂F₃N₅O₂ requires [M+H]⁺ 564.2581).

Compound 302: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzoyl)piperidin-1-yl)picolinamide

¹H nmr (CDCl₃) δ 8.17 (1H, d, J 2.5 Hz, pyH-6), 7.99 (1H, d, J 9.0 Hz, pyH-3), 7.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.79 (1H, d, J 8.5 Hz, NH), 7.66 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.52 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.22 (1H, dd, J 9.0, 2.5 Hz, pyH-4), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.07 (1H, m, pipH-4), 3.94-3.81 (7H, m, 2H of BzpipH-2, H-6, OCH₃, CH ₂C₆H₄CN), 3.45 (1H, m, BzpipH-4), 3.13 (2H, m, 2H of BzpipH-2, H-6 or 2H of pipH-2, H-6), 3.05 (2H, m, 2H of BzpipH-2, H-6 or 2H of pipH-2, H-6), 2.52 (2H, m, 2H of pipH-2, H-6), 2.10 (2H, m, 2H of pipH-3, H-5), 1.97 (4H, m, BzpipH-3, H-5), 1.91 (2H, m, 2H of pipH-3, H-5); m/z: 538 [M+H]⁺ (found [M+H]⁺, 538.2831, C₃₂H₃₅N₅O₃ requires [M+H]⁺ 538.2813).

Compound 303: 5-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-((cis)-4-(4-fluorophenoxy)cyclohexyl)picolinamide

¹H nmr (CDCl₃) δ 8.61 (1H, m, pyH-6), 8.26 (1H, d, J 8.0 Hz, pyH-3), 8.01 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.60 (2H, d, J 9.0 Hz, 2H of C₆H₄OCN), 7.00-6.94 (4H, m, 2H of C₆H₄CN, 2H of C₆H₄F), 6.86 (2H, dd, J 9.0, 4.5 Hz, 2H of C₆H₄F), 4.70 (1H, m, PhOpipH-4), 4.42 (1H, m, cHexH-1), 4.09 (1H, m, cHexH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.41 (1H, m, 1H of PhOpipH-2, H-6), 2.06-2.00 (4H, m, 2H of PhOpipH-2, H-6, 2H of cHexH-2, H-3, H-5, H-6), 1.87-1.75 (8H, 2H of PhOpipH-3, H-5, 6H of cHexH-2, H-3, H-5, H-6); ¹⁹F nmr (CDCl₃) δ −123.5; m/z: 553 [M+H]⁺ (found [M+H]⁺, 543.2429, C₃₁H₃₁FN₄O₄ requires [M+H]⁺ 543.2402).

Compound 304: 5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)-N-((cis)-4-(4-fluorophenoxy)cyclohexyl)picolinamide

¹H nmr (CDCl₃) δ 8.61 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 8.01 (1H, m, NH), 7.99 (2H, m, 2H of COC₆H₄F), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.16 (2H, t, J 9.0 Hz, 2H of COC₆H₄F), 6.97 (2H, t, J 9.0 Hz, 2H of OC₆H₄F), 6.87 (2H, dd, J 9.0, 4.5 Hz, 2H of OC₆H₄F), 4.66 (1H, m, 1H of BzpipH-2, H-6), 4.42 (1H, m, cHexH-1), 4.09 (1H, m, cHcxH-4), 3.76 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, BzpipH-4), 2.04 (2H, m, 2H of cHexH-2, H-6), 1.88-1.75 (10H, m, BzpipH-3, H-5, 6H of cHexH-2, H-3, H-5, H-6); ¹⁹F nmr (CDCl₃) δ −104.4, −123.6; m/z: 548 [M+H]⁺ (found [M+H]⁺, 548.2418, C₃₁H₃₁F₂N₃O₄ requires [M+H]548.2356).

Compound 305: N-(2-(4-fluorophenoxy)ethyl)-5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.62 (1H, m, pyH-6), 8.40 (1H, t, J 6.0 Hz, NH), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.94 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 7.90 (1H, dd, J 8.0, 1.5 Hz, pyH-4), 7.00-6.91 (4H, m, 2H of C₆H₄OCH₃, 2H of C₆H₄F), 6.87 (2H, dd, J 9.0, 4.5 Hz, 2H of C₆H₄F), 4.66 (1H, m, 1H of BzpipH-2, H-6), 4.12 (2H, t, J 5.0 Hz, CH ₂OC₆H₄F), 3.88 (2H, q, J 5.5 Hz, NHCH ₂), 3.74 (1H, m, BzpipH-2, H-6), 3.53 (1H, pentet, J 7.0 Hz, BzpipH-4), 3.15 (2H, m, 2H of BzpipH-2, H-6), 2.01 (1H, m, 1H of BzpipH-3, H-5), 1.89-1.82 (3H, m, 3H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −123.6; m/z: 506 [M+H]⁺.

Compound 306: 5-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(2-(4-fluorophenoxy)ethyl)picolinamide

¹H nmr (CDCl₃) δ 8.62 (1H, m, pyH-6), 3.39 (1H, t, J 6.0 Hz, NH), 8.26 (1H, d, J 7.5 Hz, pyH-3), 7.90 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.60 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.00-6.95 (4H, m, 2H of C₆H₄CN, 2H of C₆H₄F), 6.87 (2H, dd, J 9.0, 4.5 Hz, 2H of C₆H₄F), 4.70 (1H, m, PhOpipH-4), 4.13 (2H, t, J 5.0 Hz, CH ₂OC₆H₄F), 3.89 (4H, m, 2H of PhOpipH-2, H-6, NHCH ₂), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.40 (1H, m, 1H of PhOpipH-2, H-6), 1.94 (4H, m, PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −123.4; m/z: 489 [M+H]⁺.

Compound 307: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorobenzyloxy)azetidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.76 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 8.06 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.93 (1H, d, J 8.5 Hz, NH), 7.60 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.30 (2H, dd, J 8.5, 5.0 Hz, 2H of C₆H₄F), 7.05 (2H, t, 8.5 Hz, 2H of C₆H₄F), 4.46 (2H, m, OCH ₂C₆H₄F), 4.44 (1H, m, 1H of AzH-2, H-4), 4.38 (1H, d AB system, J 6.0 Hz, 1H of AzH-2, H-4), 4.21 (1H, m, 1H of AzH-2, H-4), 4.13 (1H, m 1H of AzH-2, H-6), 4.01 (1H, m pipH-4), 3.56 (2H, s, NCH ₂C₆H₄CN), 3.48 (1H, d, J 5.5 Hz, AzH-3), 2.81 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −113.6; m/z: 528 [M+H]⁺.

Compound 308: N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(3-(4-fluorobenzyloxy)azetidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.70 (1H, dd, J 2.0, 1.0 Hz, pyH-6), 8.16 (1H, dd, J 8.0, 1.0 Hz, pyH-3, 7.99 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (1H, d, J 8.0 Hz, NH), 7.24 (2H, dd, J 8.5, 5.0 Hz, 2H of C₆H₄F), 6.98 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.81 (2H, m, C₆H₃F₂H-2, H-6), 6.62 (1H, tt, J 9.0, 2.5 Hz, C₆H₃F₂H-4), 4.40 (2H, m, 2H of AzH-2, H-4 or CH ₂C₆H₄F), 4.37 (1H, m, 1H of AzH-2, H-4 or 1H of CH ₂C₆H₄F), 4.31 (1H, d AB system, J 6.0 Hz, 1H of AzH-2, H-4 or 1H of CH ₂C₆H₄F), 4.15 (1H, m, 1H of AzH-2, H-4), 4.05 (1H, m, 1H of AzH-2, H-4), 3.94 (1H, m, pipH-4), 3.44 (2H, s, CH ₂C₆H₃F₂), 2.98 (1H, m, AzH-3), 2.78 (2H, m, 2H of pipH-2, H-6), 2.16 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 1.95 (2H, m, pipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −110.5, −113.6; m/z: 539 [M+H]⁺.

Compound 309: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

Compound 309 was synthesized as follows:

Coupling of the benzoylpiperidine

To a mixture of 4-(4-methoxybenzoyl)piperidine hydrochloride (2.00 g, 7.82 mmol, 1.0 eq) and 5-(methoxycarbonyl)pyridine-2-carboxylic acid (1.42 g, 7.82 mmol, 1.0 eq) in dimethylformamide (55 mL) was added triethylamine (2.72 mL, 19.55 mmol, 2.5 eq) followed by HATU (2.97 g, 7.82 mmol, 1.0 eq). The reaction was stirred at room temperature for 4 hours before partitioning between EtOAc (250 mL) and water-NaHCO₃ (1:1, 200 mL). The organics were further washed with brine (150 mL), water (150 mL) and brine (150 mL), dried (Na₂SO₄) and concentrated under reduced pressure. Column chromatography (silica, 4-5% MeOH—CH₂Cl₂) yielded the coupled product (2.39 g, 80%) as a white foam; ¹H nmr (CDCl₃) δ 9.08 (1H, m, pyH-6), 8.29 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH), 7.60 (1H, d, J 8.0 Hz, pyH-3), 6.84 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.60 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1×OCH₃), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.77 (3H, s, 1×OCH₃), 3.46 (1H, m, BzpipH-4), 3.19 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 1.95-1.90 (1H, m, 1H of BzpipH-3, H-5), 1.83-1.79 (3H, m, 3H of BzpipH-3, H-5); ¹³C nmr (CDCl₃) δ 199.9, 166.6, 165.0, 163.5, 157.7, 149.6, 138.1, 130.5, 128.5, 126.3, 123.1, 113.9, 55.4, 52.5, 46.6, 42.6, 41.8, 28.8, 28.4; m/z: 383 [M+H]⁺ (found [M+H]⁺, 383.1515, C₂₁H₂₂N₂O₅ requires [M+H]⁺ 383.1602).

Hydrolysis of the Methyl Ester

To a solution of the pyridine methyl ester (2.39 g, 6.26 mmol, 1.0 eq) in tetrahydrofuran-methanol (2:1, 50 mL) was added an aqueous solution of lithium hydroxide monohydrate (0.79 g, 18.77 mmol, 3.0 eq in 10 mL of water). The reaction was stirred at room temperature for 20 minutes before neutralizing with HCl (approximately 2.4 mL of a 6M solution). The reaction was concentrated to dryness to yield the crude carboxylic acid (3.08 g) as a white solid, which was used without purification; ¹H nmr (D₆-DMSO) δ 8.97 (1H, m, pyH-6), 8.25 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.98 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.51 (1H, dd, J 8.0, 1.0 Hz, pyH-3), 7.04 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.50 (1H, m, 1H of BzpipH-2, H-6), 3.83 (3H, s, 1×OCH₃), 3.76-3.62 (2H, m, 1H of BzpipH-2, H-6, BzpipH-4), 3.20 (1H, m, 1H of BzpipH-2, H-6), 3.00 (1H, m, 1H of BzpipH-2, H-6), 1.86 (1H, m, 1H of BzpipH-3, H-5), 1.68 (1H, m, 1H of BzpipH-3, H-5), 1.54 (2H, m, 2H of BzpipH-3, H-5); m/z: 369 [M+H]⁺.

Coupling of the Benzylaminopiperidine

To a suspension of the crude pyridine carboxylic acid (3.08 g, 6.26 mmol, 1.0 eq) and 1-(4-cyanobenzyl)-4-aminopiperidine dihydrochloride (1.80 g, 6.26 mmol, 1.0 eq) in dimethylformamide (50 mL) was added triethylamine (3.05 mL, 21.91 mmol, 3.5 eq). HATU (2.38 g, 6.26 mmol, 1.0 eq) was added forming a yellow solution, which was stirred at room temperature for 6 hours. The reaction was partitioned between EtOAc (200 mL) and water-NaHCO₃ (1:1, 200 mL). The organics were washed with brine (150 mL), water (150 mL) and brine (150 mL) before drying (Na₂SO₄) and concentrating under reduced pressure. MPLC (2-5% MeOH—CH₂Cl₂) yielded Compound 309 (2.93 g, 83% over two steps) as a white solid ¹H nmr (CDCl₃) δ 8.84 (1H, d, J 2.0 Hz, pyH-6), 8.06 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.88 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 7.56 (1H, d, J 7.5 Hz, pyH-3), 7.54 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.38 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.89 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.24 (1H, d, J 7.5 Hz, NH), 4.63 (1H, m, 1H of BzpipH-2, H-6), 3.98 (1H, m, pipH-4), 3.87 (1H, m, 1H of BzpipH-2, H-6), 3.81 (3H, s, OCH₃), 3.50 (2H, s, CH ₂C₆H₄CN), 3.47 (1H, m, BzpipH-4), 3.19 (1H, m, 1H of BzpipH-2, H-6), 3.04 (1H, ddd, J 11.5, 10.0, 3.0 Hz, 1H of BzpipH-2, H-6), 2.77 (2H, m, 2H of pipH-2, H-6), 2.14 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 1.97 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.85-1.72 (3H, m, 3H of BzpipH-3, H-5), 1.56 (2H, m, 2H of pipH-2, H-6); ¹³C nmr (CDCl₃) δ 200.0, 167.0, 164.6, 163.7, 155.9, 147.4, 144.6, 135.9, 132.1, 130.9, 130.6, 129.3, 128.5, 122.8, 119.0, 114.0, 110.8, 62.4, 55.5, 52.5, 47.4, 46.7, 42.6, 42.0, 32.0, 28.8, 28.5; m/z: 566 [M+H]⁺ (found [M+H]⁺, 566.2749, C₃₃H₅₅N₅O₄ requires [M+H]⁺ 566.2762).

Compound 310: (N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.58 (1H, d, J 8.0 Hz, pyH-3), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.87 (2H, d, J 6.0 Hz, C₆H₃F₂H-2, H-6), 6.67 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4), 6.52 (1H, d, J 7.5 Hz, NH), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH-4), 3.92 (1H, m, 1H, BzpipH-2, H-6), 3.87 (3H, s, OCH₃), 3.53 (1H, m, BzpipH-4), 3.48 (2H, s, CH₂C₆H₃F₂), 3.25 (1H, m, 1H of BzpipH-2, H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.19 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.92-1.76 (3H, m, 3H of BzpipH-3, H-5), 1.63 (3H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −110.5; m/z: 578 [M+H]⁺.

Compound 311: N-((cis)-4-(4-fluorophenoxy)cyclohexyl)-5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.61 (1H, d, J 1.5 Hz, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 8.01 (1H, d, J 8.5 Hz, NH), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.00-6.94 (4H, m, 2H of C₆H₄OCH₃, 2H of C₆H₄F), 6.87 (2H, dd, J 9.0, 4.5 Hz, 2H of C₆H₄F), 4.66 (1H, m, 1H of BzpipH-2, H-6), 4.42 (1H, m, cHexH-1), 4.09 (1H, m, cHexH-4), 3.88 (3H, s, OCH₃), 3.78 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, BzpipH-4), 3.16 (2H, m, 2H of BzpipH-2, H-6), 2.07-2.02 (3H, m, 3H of cHexH-2, H-4, H-5, H-6, BzpipH-3, H-5), 1.90-1.75 (9H, m, 9H of cHexH-2, H-3, H-5, H-6, BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −123.6; m/z: 560 [M+H]⁺.

Compound 312: N-((cis)-4-(4-fluorophenoxy)cyclohexyl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.61 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 8.01 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.01-6.94 (4H, m, 2×2H of C₆H₄F), 6.89-6.84 (4H, m, 2×2H of C₆H₄F), 4.52 (1H, m, cHexH-1 or PhOpipH-4), 4.42 (1H, m, cHexH-1 or PhOpipH-4), 4.09 (1H, m, cHexH-4)), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.36 (1H, m, 1H of PhOpipH-2, H-6), 2.06-1.75 (12H, m, PhOpipH-3, H-5, cHexH-2, H-3, H-5, H-6); ¹⁹F nmr (CDCl₃) δ −122.5, −123.5; m/z: 536 [M+H]⁺ (found [M+H]⁺, 536.2416, C₃₀H₃₁F₂N₃O₄ requires [M+H]⁺ 536.2356).

Compound 313: 5-(3-(4-cyanophenoxy)azetidine-1-carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.74 (1H, m, pyH-6), 8.19 (1H, d, J 8.0 Hz, pyH-3), 8.03 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.86 (1H, m, NH), 7.55 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.82 (2H, d, J 6.0 Hz, C₆H₃F₂H-2, H-6), 6.75 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.62 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4), 5.02 (1H, m, AzH-3), 4.61 (2H, dd, J 10.5, 6.0 Hz, 2H of AzH-2, H-4), 4.27 (2H, m, 2H of AzH-2, H-4), 3.94 (1H, m, pipH-4), 3.42 (2H, s, CH ₂C₆H₃F₂), 2.76 (2H, m, 2H of pipH-2, H-6), 2.15 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 1.95 (2H, m, 2H of pipH-3, H-5), 1.58 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ; m/z: 533 [M+H]⁺ (found [M+H]⁺, 532.2160, C₂₉H₂₇F₂N₅O₃ requires [M+H]⁺ 532.2155).

Compound 314: 5-(3-(4-cyanophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.71 (1H, d, J 2.5 Hz, pyH-6), 8.30 (1H, d, J 8.0 Hz, pyH-3), 8.00 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.93 (1H, d, J 8.5 Hz, NH), 7.92 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.86 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.88 (2H, d, J 6.0 Hz, C₆H₃F₂H-2, H-6), 6.68 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4), 5.07 (2H, br s, 2H of triazolopyrazine), 4.27 (2H, br s, 2H of triazolopyrazine), 4.14 (2H, m, 2H of triazolopyrazine), 4.02 (1H, m, pipH-4), 3.49 (2H, s, CH ₂C₆H₃F₂), 2.84 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.03 (2H, m, 2H of pipH-3, H-5), 1.68 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −110.5; m/z: 583 [M+H]⁺.

Compound 315: N-((1s,4s)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.92 (1H, d, J 1.5 Hz, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.5 Hz, 2H of C₆H₄OCH₃), 7.61 (1H, d, J 8.0 Hz, pyH-3), 7.57 (2H, d, J 2H of C₆H₄CN), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.43 (1H, d, J 8.0 Hz, NH), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.62 (1H, m, cHexH-1), 4.12 (1H, m, cHexH-4), 3.93 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.53 (1H, m, BzpipH-4), 3.25 (1H, m, 1H of BzpipH-2, H-6), 3.10 (1H, m, 1H of BzpipH-2, H-6), 2.11 (2H, m, 2H of cHexH-2, H-6), 2.04-1.73 (10H, m, 2H of cHexH-2, H-6, cHexH-3, H-5, BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −61.6, −114.9; m/z: 568 [M+H]⁺ (found [M+H]⁺, 567.2632, C₃₃H₃₄N₄O₅ requires [M+H]⁺ 567.2602).

Compound 316: N-((cis)-4-(4-fluorophenoxy)cyclohexyl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.93 (1H, d, J 1.5 Hz, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.65 (1H, dd, J 8.0, 0.5 Hz, pyH-3), 7.00-6.94 (4H, m, 2H of C₆H₄OCH₃, 2H of C₆H₄F), 6.86 (2H, dd, J 9.0, 4.5 Hz, 2H of C₆H₄F), 6.29 (1H, d, J 8.0 Hz, NH), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.44 (1H, m, cHexH-1), 4.11 (1H, m, cHexH-4), 3.95 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.52 (1H, m, BzpipH-4), 3.26 (1H, ddd, J 10.5, 10.0, 3.5 Hz, 1H of BzpipH-2, H-6), 3.10 (ddd, J 11.5, 10.0, 3.0 Hz, 1H of BzpipH-2, H-6), 2.09-1.73 (12H, m, BzpipH-3, H-5, cHexH-2, H-3, H-5, H-6); ¹⁹F nmr (CDCl₃) δ −123.4; m/z: 560 [M+H]+(found [M+H]⁺, 560.2511, C₂H₃₄FN₃O₅ requires [M+H]⁺ 560.2555).

Compound 317: N-(1-(4-fluorobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.30-7.25 (2H, m, 2H of C₆H₄F), 7.02-6.94 (4H, m, 2H of C₆H₄OCH₃, 2H of C₆H₄F), 6.32 (1H, d, J 8.5 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.03 (1H, m, pipH-4), 3.93 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.52 (1H, m, BzpipH-4), 3.47 (2H, s, CH₂C₆H₄F), 3.25 (1H, d, J 11.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.10 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.16 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.93-1.81 (3H, m, 3H of BzpipH-3, H-5), 1.68-1.54 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −115.9; m/z: 560 [M+H]⁺ (found [M+H]⁺, 559.2708, C₃₂H₃₅FN₄O₄ requires [M+H]⁺ 538.2715).

Compound 318: 6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of COC₆ H ₄OCH₃), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.22 (2H, d, J 8.5 Hz, 2H of CH₂C₆ H ₄OCH₃), 6.95 (2H, d, J 9.0 Hz, 2H of COC₆ H ₄OCH₃), 6.85 (2H, d, J 8.5 Hz, 2H of CH₂C₆ H ₄OCH₃), 6.30 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH-4), 3.93 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1×OCH₃), 3.80 (3H, s, 1×OCH₃), 3.52 (1H, m, BzpipH-4), 3.45 (2H, s, CH ₂C₆H₄OCH₃), 3.25 (1H, m, 1H of BzpipH-2, H-6), 3.10 (1H, ddd, J 12.0, 10.0, 3.0 Hz, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.14 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.92-1.81 (3H, m, 3H of BzpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5); m/z: 571 [M+H]⁺ (found [M+H]⁺, 571.2895, C₃₃H₃₈N₄O₅ requires [M+H]⁺ 571.2915).

Compound 319: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, d, J 1.5 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃ or C₆H₄CN), 7.23 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃ or C₆H₄CN), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃ or C₆H₄CN), 6.85 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃ or C₆H₄CN), 6.43 (1H, d, J 7.5 Hz, NH), 4.69 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.79 (3H, s, OCH₃), 3.70 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (1H, m, 1H of PhOpipH-2, H-6), 3.48 (2H, s, CH ₂C₆H₄OCH₃), 2.88 (2H, m, 2H of pipH-2, H-6), 2.16 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.03-1.93 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.86 (1H, m, 1H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); m/z: 554 [M+H]⁺.

Compound 320: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.86 (1H, d, J 1.5 Hz, pyH-6), 8.10 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.64 (1H, d, J 8.5 Hz, pyH-3), 7.53 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.25 (2H, m, 2H of C₆H₄F), 6.96 (1H, t, J 8.5 Hz, 2H of C₆H₄F), 6.90 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.16 (1H, m, NH), 4.63 (1H, m, PhOpipH-4), 3.99 (1H, m, pipH-4), 3.84 (2H, m, 2H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (2H, s, CH ₂C₆H₄F), 3.48 (1H, m, 1H of PhOpipH-2, H-6), 2.88 (2H, m, 2H of pipH-2, H-6), 2.19 (2H, m, 2H of pipH-2, H-6), 2.02-1.92 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.60 (2H, m, 2H of pipH-3, H-5); m/z: 543 [M+H]⁺.

Compound 321: N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.93 (1H, d, J 2.0 Hz, pyH-6), 8.15 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.62 (1H, d, J 8.5 Hz, pyH-3), 7.58 (2H, d, J 8.5 Hz, 2H of 1×C₆H₄CN), 7.56 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 6.95 (2H, d, J 8.5 Hz, 2H of 1×C₆H₄CN), 6.93 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 6.57 (1H, d, J 8.0 Hz, NH), 4.69 (1H, pentet, J 3.0 Hz, PhOpipH-4), 4.61 (1H, m, cHexH-1), 4.10 (1H, m, cHexH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.70 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (1H, m, 1H of PhOpipH-2, H-6), 2.11-2.04 (3H, m, 3H of PhOpipH-3, H-5, cHexH-2, H-3, H-5, H-6), 1.98-1.73 (9H, m, 9H of PhOpipH-3, H-5, cHexH-2, H-3, H-5, H-6); m/z: 550 [M+H]⁺.

Compound 322: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.84 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.59 (1H, d, J 8.0 Hz, pyH-3), 7.53 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.90 (2H, d, J 9.5 Hz, 2H of C₆H₄CN), 6.80 (2H, m, C₆H₃F₂H-2, H-6), 6.62 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4), 6.21 (1H, d, J 8.0 Hz, NH), 4.64 (1H, heptet, J 3.0 Hz, PhOpipH-4), 3.96 (1H, m, pipH-4), 3.85 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, ddd, J 13.0, 9.0, 3.5 Hz, 1H of PhOpipH-2, H-6), 3.47 (1H, m, 1H of PhOpipH-2, H-6), 3.42 (2H, s, CH ₂C₆H₃F₂), 2.78 (2H, m, 2H of pipH-2, H-6), 2.13 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.00-1.95 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.81 (1H, m, 1H of PhOpipH-3, H-5), 1.56 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −110.5; m/z: 560 [M+H]⁺.

Compound 323: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.63 (1H, d, J 8.0 Hz, pyH-3), 7.61 (2H, d, J 8.5 Hz, 2H of 1×C₆H₄CN), 7.58 (2H, d, J 8.5 Hz, 2H of 1×C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 1×C₆H₄CN), 6.96 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 6.94 (1H, d, J 8.0 Hz, NH), 4.70 (1H, pentet, J 3.0 Hz, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.70 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 2.83 (2H, m, 2H of pipH-2, H-6), 2.20 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.02 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.87 (1H, m, 1H of PhOpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); m/z: 549 [M+H]⁺.

Compound 324: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-((cis)-4-(4-fluorophenoxy)cyclohexyl)nicotinamide

¹H nmr (CDCl₃) δ 8.94 (1H, d, J 1.5 Hz, pyH-6), 8.16 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.67 (1H, d, J 8.5 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.97 (4H, m, 2H of C₆H₄CN, 2H of C₆H₄F), 6.85 (2H, m, 2H of C₆H₄F), 6.28 (1H, d, J 8.5 Hz, NH), 4.70 (1H, m, PhOpipH-4), 4.44 (1H, br s, cHexH-1), 4.11 (1H, m, cHcxH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.54 (1H, m, 1H of PhOpipH-2, H-6), 2.09-1.98 (5H, m, 5H of cHexH-2, H-3, H-5, H-6, PhOpipH-3, -5), 1.90-1.73 (7H, m, 7H of cHexH-2, H-3, H-5, H-6, PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −123.3; m/z: 543 [M+H]⁺ (found [M+H]⁺, 543.2511, C₃₁H₃₁FN₄O₄ requires [M+H]⁺ 543.2402).

Compound 325: N-(6-(4-fluorophenoxy)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 9.57 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.47 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.32 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.42 (1H, d, J 8.0 Hz, pyH-3), 7.11-7.06 (4H, m, 2H of C₆H₄OCH₃, 2H of C₆H₄F), 6.97-6.93 (3H, m, 2H of C₆H₄F, N, O-pyH-3), 4.68 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.81 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, BzpipH-4), 3.28-3.11 (2H, m, 2H of BzpipH-2. H-6), 2.02 (1H, m, 1H of BzpipH-3, H-5), 1.92-1.82 (3H, m, 3H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −118.6; m/z: 555 [M+H]⁺ (found [M+H]⁺, 555.2267, C₃₁H₂₇FN₄O₅ requires [M+H]⁺ 555.2039).

Compound 326: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide

¹H nmr (CDCl₃) δ 9.42 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.42 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.33 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.60 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.44 (1H, d, J 8.0 Hz, pyH-3), 7.08 (4H, m, 2H of C₆H₄CN, 2H of C₆H₄F), 6.97-6.94 (3H, m, 2H of C₆H₄F, N, O-pyH-3), 4.71 (1H, m, PhOpipH-4), 3.99 (1H, m, 1H of PhOpipH-2, 6), 3.86 (1H, m, 1H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.44 (1H, m, 1H of PhOpipH-2, H-6), 2.07-1.94 (3H, m, 3H of PhOpipH-3, H-5), 1.88 (1H, m, 1H of PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −118.3; m/z: 538 [M+H]⁺ (found [M+H]⁺, 538.1985, C₃₀H₂₄FN₅O₄ requires [M+H]⁺ 538.1885).

Compound 327: 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.89 (1H, d, J 1.5 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.62 (1H, d, J 7.5 Hz, pyH-3), 7.30-7.21 (4H, m, 2H of C₆H₄F, 2H of C₆H₄OCH₃), 7.00 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.86 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.34 (1H, d, J 8.0 Hz, NH), 4.02 (1H, m, pipH-4), 3.80 (5H, m, 2H of piz, OCH₃), 3.52 (2H, m, 2H of piz), 3.50 (2H, s, CH ₂C₆H₄F or CH ₂C₆H₄OCH₃), 3.49 (2H, s, CH ₂C₆H₄F or CH ₂C₆H₄OCH₃), 2.89 (2H, m, 2H of pipH-2, H-6), 2.54 (2H, t, J 5.0 Hz, 2H of piz), 2.41 (2H, m, t, J 5.0 Hz, 2H of piz), 2.19 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −115.5; m/z: 546 [M+H]⁺.

Compound 328: 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.92 (1H, m, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.36-7.25 (4H, m, 2×2H of C₆H₄F), 7.06-6.97 (4H, m, 2×2H of C₆H₄F), 6.60 (1H, d, J 7.0 Hz, NH), 4.06 (1H, m, pipH-4), 3.80 (2H, t, J 5.0 Hz, 2H of piz), 3.63 (2H, s, 1×CH₂C₆H₄F), 3.51 (4H, m, 2H of piz, 1×CH₂C₆H₄F), 2.99 (2H, m, 2H of pipH-2, H-6), 2.54 (2H, t, J 5.0 Hz, 2H of piz), 2.41 (2H, t, J 5.0 Hz, 2H of piz), 2.33 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.06 (2H, m, 2H of pipH-3, H-5), 1.75 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −114.5, −115.4; m/z: 534 [M+H]⁺.

Compound 329: 5-(4-(3,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.52 (1H, m, pyH-6), 8.16 (1H, d, J 8.0 Hz, pyH-3), 7.84 (1H, d, J 7.0 Hz, NH), 7.79 (2H, m, pyH-4, 1H of C₆H₃F₂), 7.87 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.93 (1H, m, 1H of C₆H₃F₂), 6.85 (1H, m, 1H of C₆H₃F₂), 6.79 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 4.57 (1H, m, BzpipH-4), 3.93 (1H, m, pipH-4), 3.73 (3H, s, OCH₃), 3.65 (1H, m, 1H of BzpipH-2, H-6), 3.42 (2H, s, CH ₂C₆H₄OCH₁), 3.34 (1H, m, BzpipH-4), 3.06 (2H, m, 2H of BzpipH-2, H-6), 2.79 (2H, m, 2H of pipH-2, H-6), 2.13 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 1.97-1.80 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.75-1.52 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5) ¹⁹F nmr (CDCl₃) δ −101.2, −106.6; m/z: 577 [M+H]⁺.

Compound 330: 5-(4-(3,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 8.77 (1H, m, 1×ArH), 8.51 (1H, d, J 2.5 Hz, 1×ArH), 8.45 (2H, dd, J 5.0, 3.5 Hz, 2×ArH), 8.42 (1H, s, 1×ArH), 8.05 (1H, dd, J 8.0, 2.0 Hz, 1×ArH), 7.99 (1H, m, 1×ArH), 7.22-7.18 (4H, m, 4×ArH), 7.15-6.56 (3H, m, 3×ArH), 4.75 (1H, m, 1H of BzpipH-2, H-6), 3.84 (1H, m, 1H of BzpipH-2, H-6), 3.53 (1H, m, BzpipH-4), 3.33-3.22 (2H, m, 2H of BzpipH-2, H-6), 2.07-2.02 (2H, m, 2H of BzpipH-3, H-5), 1.86 (2H, m, 2H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.1, −106.5, −118.6; m/z: 561 [M+H]⁺.

Compound 331: 5-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.59 (1H, d, J 1.5 Hz, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.92-7.84 (3H, m, NH, pyH-4, 1H of C₆H₃F₂), 7.24 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.00 (1H, m, 1H of C₆H₃F₂), 6.88 (1H, m, 1H of C₆H₃F₂), 6.86 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.64 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m pipH-4), 3.80 (3H, s, OCH₃), 3.74 (1H, m, BzpipH-2, H-6), 3.48 (2H, s, CH ₂C₆H₄OCH₃), 3.41 (1H, m, BzpipH-4), 3.13 (2H, m, 2H of BzpipH-2, H-6), 2.86 (2H, m, 2H of pipH-2, H-6), 2.19 (2H, dd, J 11.0, 8.5 Hz, 2H of pipH-2, H-6), 1.99 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.76-1.63 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.3, −11.6.5; m/z: 577 [M+H]⁺.

Compound 332: N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, d, J 1.5 Hz, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.67 (1H, d, J 8.0 Hz, pyH-3), 7.58 (2H, d, J 9.0 Hz, C₆H₄CN), 7.28 (2H, m, 2H of C₆H₄F), 7.00 (2H, t, J 9.0 Hz, 2H of C₆H₄F), 6.95 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.19 (1H, d, J 8.0 Hz, NH), 4.62 (1H, m, cHexH-1), 4.12 (1H, m, cHexH-4), 3.82 (2H, m, 2H of piz), 3.51 (4H, m, 2H of piz, CH ₂C₆H₄F), 2.55 (2H, m, 2H of piz), 2.42 (2H, m, 2H of piz), 2.10 (2H, m, 2H of cHexH-2, H-6), 1.94 (2H, m, 2H of cHexH-2, H-6 or 2H of cHexH-3, H-5), 1.84-1.71 (4H, 2H of cHexH-3, H-5, 2H of cHexH-2, H-6 or cHexH-3, H-5); ¹⁹F nmr (CDCl₃) δ −115.5; m/z: 542 [M+H]⁺.

Compound 333: tert-butyl 4-(6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)nicotinamido)piperidine-1-carboxylate

¹H nmr (CDCl₃) δ 8.91 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.58 (2H, d, J 9.5 Hz, 2H of C₆H₄CN), 7.51 (1H, d, J 8.5 Hz, pyH-3), 7.21 (1H, d, J 8.0 Hz, NH), 6.94 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 4.68 (1H, m, PhOpipH-4), 4.09 (3H, m, 3H of PhOpipH-2, H-6, pipH-2, H-4, H-6), 3.94-3.80 (2H, m, 2H of PhOpipH-2, H-6, pipH-2, H-4, H-6), 3.07-3.62 (1H, m, 1H of PhOpipH-2, H-6, pipH-2, H-4, H-6), 3.44 (1H, m, 1H of PhOpipH-2, H-6, pipH-2, H-4, H-6), 2.85 (2H, t, J 12.0 Hz, 2H of pipH-2, H-6), 2.10-1.80 (8H, m, PhOpipH-3, H-5, pipH-3, H-5), 1.45 (9H, s, C(CH₃)₃); m/z: 534 [M+H]⁺, 478 [M+H—C₄H₈]⁺.

Compound 334: 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide

¹H nmr (CDCl₃) δ 9.56 (1H, s, NH), 8.83 (1H, d, J 2.0 Hz, N, O-pyH-6), 8.38 (1H, d, J 2.5 Hz, pyH-6), 8.27 (1H, dd, J 8.5, 2.5 Hz, pyH-4), 8.00 (1H, dd, J 8.5, 2.0 Hz, N, O-pyH-4), 7.31 (1H, d, J 8.0 Hz, N, O-pyH-3), 7.20 (2H, m, 2H of 1×C₆H₄F), 7.03 (4H, m, 4H of 1×C₆H₄F), 6.94 (2H, t, J 9.0 Hz, 2H of 1×C₆H₄F), 6.88 (1H, d, J 9.0 Hz, pyH-3), 3.76 (2H, m, 2H of piz), 3.44 (2H, s, CH ₂C₆H₄F), 3.36 (2H, m, 2H of piz), 2.47 (2H, m, 2H of piz), 2.33 (2H, m, 2H of piz); ¹⁹F nmr (CDCl₃) δ −115.3, −118.5; m/z: 530 [M+H]⁺.

Compound 335: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.58 (3H, m, 2H of C₆H₄CN. NH), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.68 (1H, d, J 8.0 Hz, pyH-3), 4.69 (1H, m, PhOpipH-4), 4.07 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.69 (1H, m, 1H of PhOpipH-2, H-6), 3.47 (1H, m, 1H of PhOpipH-2, H-6), 3.12 (2H, m, 2H of pipH-2, H-6), 2.74 (2H, m, 2H of pipH-2, H-6), 2.10-1.81 (6H, m, PhOpipH-3, H-5, 2H of pipH-3, H-5), 1.48 (2H, m, 2H of pipH-3, H-5); m/z: 434 [M+H]⁺.

Compound 336: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1-yl)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.95 (1H, d, J 1.5 Hz, pyH-6), 8.19 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.67 (1H, d, J 8.0 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.20 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.72 (1H, d, J 7.0 Hz, NH), 6.53 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 4.69 (1H, m, PhOpipH-4), 4.08 (1H, m, pipJ=4), 3.93-3.86 (2H, m, 2 h of PhOpipH-2, H-6), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.65 (2H, s, CH₂C₆H₄N), 3.50 (1H, m, PhOpipH-2, H-6), 3.28 (4H, m, pyrrolidineH-2, H-5), 3.09 (2H, m, 2H of pipH-2, H-6), 2.35 (6H, m, 2H of pipH-2, H-6, pyrrolidineH-3, H-4), 2.08-1.86 (8H, m, pipH-3, H-5, PhOpipH-3, H-5); m/z: 594 [M+H]⁺.

Compound 337: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-morpholinobenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.92 (1H, m, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.69 (1H, d, J 8.5 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.25 (2H, m, 2H of C₆H₄N), 6.96 (2H, d, J 9.5 Hz, 2H of C₆H₄CN), 6.88 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 6.29 (1H, d, J 7.0 Hz, NH), 4.70 (1H, m, PhOpipH-4), 4.04 (1H, m, pipH-4), 3.91 (2H, m, 2H of PhOpipH-2, H-6), 3.87, 3.85 (4H, d AB system, J 5.0 Hz, 2×morpholineH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.55 (3H, m, CH₂C₆H₄N, 1H of PhOpipH-2, H-6), 3.17, 3.15 (4H, d AB system, J 4.5 Hz, 2×morpholineH-3, H-5), 2.96 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, dd, J 12.0, 10.5 Hz, 2H of pipH-2, H-6), 2.02 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.81-1.69 (4H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5); m/z: 610 [M+H]⁺.

Compound 338: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.92 (1H, d, J 2.0 Hz, pyH-6), 8.16 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.69 (1H, d, J 8.0 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.38 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 7.18 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.22 (1H, m, NH), 4.70 (1H, m, PhOpipH-4), 4.06 (1H, m, pipH-4), 3.94-3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.58 (2H, s, CH ₂C₆H₄OCF₃), 3.50 (1H, m, PhOpipH-2, H-6), 2.93 (2H, m, 2H of pipH-2, H-6), 2.25 (2H, dd, J 11.5, 10.5 Hz, 2H of pipH-2, H-6), 2.05 (4H, m, pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.84-1.67 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.9; m/z: 609 [M+H]⁺.

Compound 339: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.63 (1H, m, pyH-6), 8.27 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, m, NH), 7.92 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄CF₃), 7.51 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆-4CF₃), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄CF₃), 6.94 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄CF₃), 4.00 (3H, m, pipH-4, 2H of piz), 3.57 (4H, m, CH₂C₆H₄CN, 2H of piz), 3.31 (4H, m, 4H of piz), 2.82 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (H, m, 2H of pipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −61.6; m/z: 577 [M+H]⁺.

Compound 340: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-cyanophenyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.63 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.90 (2H, m, NH, pyH-4), 7.60 (2H, d, J 8.5 Hz, 2H of 1×C₆H₄CN), 7.52 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of 1×C₆H₄CN), 6.87 (2H, d, J 9.5 Hz, 2H of 1×C₆H₄CN), 4.03-3.90 (3H, m, pipH-4, 2H of piz), 3.60 (2H, m, 2H of piz), 3.56 (2H, s, CH ₂C₆H₄CN), 3.36 (4H, m, 4H of piz), 2.80 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.01 (2H, m, 2H of pipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 534 [M+H]⁺.

Compound 341: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenyl)piperazine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.63 (1H, m, pyH-6), 8.26 (1H, dd, J 8.0, 1.0 Hz, pyH-3), 7.93 (1H, d, J 8.0 Hz, NH), 7.91 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.62 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.99 (2H, m, 2H of C₆H₄F), 6.89 (2H, m, 2H of C₆H₄F), 3.99 (3H, m, pipH-4, 2H of piz), 3.57 (3H, m, CH ₂C₆H₄CN, 2H of piz), 3.18 (2H, m, 2H of piz), 3.07 (2H, m, 2H of piz), 2.82 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, mdd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.03 (2H, m, 2H of pipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −122.6; m/z: 527 [M+H]⁺.

Compound 342: 5-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 9.90 (1H, s, NH), 8.67 (1H, m, 1×pyH-6), 8.41 (1H, d, J 2.0 Hz, 1×pyH-6), 8.36-8.33 (2H, m, 2×pyH), 7.95 (1H, dd, J 8.0, 2.0 Hz, 1×pyH-4), 7.89 (1H, m, 1H of C₆H₃F₂), 7.13-7.08 (4H, m, 4H of C₆H₄F), 7.00 (1H, m, 1H of C₆H₃F₂), 6.97 (1H, d, J 9.0 Hz, 1×pyH-3), 6.90 (1H, ddd, J 11.5, 9.0, 2.5 Hz, 1H of C₆H₃F₂), 4.64 (1H, m, 1H of BzpipH-2, H-6), 3.75 (1H, m, 1H of BzpipH-2, H-6), 3.43 (1H, m, BzpipH-4), 3.19 (1H, m, 1H of BzpipH-2, H-6), 3.12 (1H, m, 1H of BzpipH-2, H-6), 2.08 (1H, m, 1H of BzpipH-3, H-5), 1.90 (1H, m, 1H of BzpipH-3, H-5), 1.78 (2H, m, 2H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.1, −116.5, −118.6; m/z: 562 [M+H]⁺ (found [M+H]⁺, 561.1844, C₃₂H₃₅N₅O₃ requires [M+H]⁺ 561.1744).

Compound 343: 6-(4-(2,4-difluorophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide

¹H nmr (CDCl₃) δ 9.79 (1H, s, NH), 8.92 (1H, m, pyH-6), 8.47 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.34 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.08 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.36 (1H, d, J 8.0 Hz, pyH-3), 7.11-7.01 (4H, m, C₆H₄F), 6.99-6.92 (2H, m, N, O-pyH-3, 1H of C₆H₃F₂), 6.90-6.76 (2H, m, 2H of C₆H₃F₂), 4.47 (1H, m, PhOpipH-4), 3.92 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 1H of PhOpipH-2, H-6), 3.35 (1H, m, 1H of PhOpipH-2, H-6), 1.98 (2H, m, 2H of PhOpipH-3, H-5), 1.93-1.80 (2H, m, 2H of PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −117.4, −118.5, −127.3; m/z: 549 [M+H]⁺.

Compound 344: 6-(4-(2,4-difluorophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.21 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.57 (1H, d, J 8.0 Hz, pyH-3), 7.25 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.97 (1H, td, J 9.0, 5.5 Hz, 1H of C₆H₃F₂), 6.89-6.75 (4H, m, 2H of C₆H₄OCH₃, 2H of C₆H₃F₂), 4.45 (1H, m, PhOpipH-4), 4.03 (1H, m, 1H of pipH-4), 3.92-3.85 (2H, m, 2H of PhOpipH-2, H-6), 3.79 (3H, s, OCH₃), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH ₂C₆H₄OCH₃), 3.44-3.37 (1H, m, 1H of PhOpipH-2, H-6), 2.97 (2H, m, 2H of pipH-2, H-6), 2.27 (2H, dd, J 11.5, 10.5 Hz, 2H of pipH-2, H-6), 2.04-1.90 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.83 (1H, m, 1H of PhOpipH-3, H-5), 1.72 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −117.7, −127.3; m/z: 565 [M+H]⁺.

Compound 345: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(2,4-difluorophenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.65 (1H, d, J 8.5 Hz, pyH-3), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.98 (1H, dt, J 5.0, 9.0 Hz, 1H of C₆H₃F₂H-5 or H-6), 6.86 (1H, m, 1H of C₆H₃F₂H-3), 6.79 (1H, m, 1H of C₆H₃F₂H-5 or H-6), 6.24 (1H, d, J 8.0 Hz, NH), 4.47 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.95-3.87 (2H, m, 2H of PhOpipH-2, H-6), 3.75 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH ₂C₆H₄CN), 3.42 (1H, m, 1H of PhOpipH-2, H-6), 2.84 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.06-1.92 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.86 (1H, m, 1H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −117.6, −127.3; m/z: 560 [M+H]⁺.

Compound 346: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.89 (1H, m, pyH-6), 8.10 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.87 (1H, dt, J 6.5, 8.5 Hz, 1H of C₆H₃F₂), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.58 (1H, m, pyH-3), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.99 (1H, ddd, J 9.5, 9.0, 2.5 Hz, 1H of C₆H₃F₂), 6.89 (1H, m, 1H of C₆H₃F₂), 6.50 (1H, d, J 8.0 Hz, NH), 4.67 (1H, m, 1H of BzpipH-2, H-6), 4.02 (1H, m, pipH-4), 3.89 (1H, m, 1H of BzpipH-2, H-6), 3.56 (3H, s, CH ₂C₆H₄CN), 3.40 (1H, m, BzpipH-4), 3.21 (1H, m, BzpipH-2, H-6), 3.08 (1H, ddd, J 11.5, 10.5, 3.0 Hz, 1H of BzpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.08-2.01 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.89-1.72 (3H, m, 3H of BzpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.5, −106.5; m/z: 572 [M+H]⁺.

Compound 347: 6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.86 (1H, dt, J 6.5, 8.5 Hz, 1H of C₆H₃F₂), 7.59 (1H, d, J 8.0 Hz, pyH-3), 7.23 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.98 (1H, m, 1H of C₆H₃F₂), 6.92-6.84 (3H, m, 2H of C₆H₄OCH₃, 1H of C₆H₃F₂), 6.39 (1H, d, J 7.5 Hz, NH), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.89 (1H, m, 1H of BzpipH-2, H-6), 3.80 (3H, s, OCH₃), 3.51 (2H, s, CH ₂C₆H₄OCH₃), 3.39 (1H, m, BzpipH-4), 3.21 (1H, ddd, J 10.5, 9.0, 3.0 Hz, 1H of BzpipH-2, H-6), 3.08 (1H, m, 1H of BzpipH-2, H-6), 2.90 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.03 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.89-1.76 (2H, m, 2H of BzpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.6, −106.5; m/z: 577 [M+H]⁺.

Compound 348: 6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide

¹H nmr (CDCl₃) δ 9.81 (1H, s, NH), 8.91 (1H, m, pyH-6), 8.48 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.34 (1H, dd, J 8.5, 2.5 Hz, N, O-pyH-4), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (1H, dt, J 8.5, 6.5 Hz, 1H of C₆H₃F₂), 7.35 (1H, d, J 8.0 Hz, pyH-3), 7.10-6.85 (3H, m, N, O-pyH-3, 2H of C₆H₃F₂), 4.65 (1H, m, 1H of BzpipH-2, H-6), 3.78-3.73 (1H, m, 1H of BzpipH-2, H-6), 3.40 (1H, m, BzpipH-4), 3.23-3.07 (2H, m, 2H of BzpipH-2, H-6), 2.08 (1H, m, 1H of BzpipH-3, H-5), 1.90-1.74 (3H, m, 3H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.3, −106.5, −118.6; m/z: 561 [M+H]⁺.

Synthesis of Compounds 349 and 350 Coupling of the 1-tert-Butyloxycarbonyl-3-Fluoro-4-aminopiperidine

To a mixture of the crude pyridine carboxylic acid (2.15 g of approximately 66% purity, 3.86 mmol, 1.0 eq) and 1-tert-butyl-3-fluoro-4-aminopiperidine (0.84 g, 3.86 mmol, 1.0 eq) was added dimethylformamide (40 mL) followed by triethylamine (1.31 mL, 9.64 mmol, 2.5 eq). After the addition of HATU (1.47 g, 3.86 mmol, 1.0 eq) the reaction was stirred at room temperature for 4 hours before partitioning between EtoAc (300 mL) and water-NaHCO₃ (1:1, 300 mL). The organics were further washed with brine (250 mL), water (300 mL) and brine (250 mL) before drying (Na₂SO₄) and concentrating under reduced pressure. MPLC (0→10% MeOH—CH₂Cl₂) yielded the coupled material (1.41 g, 64%) as a pale yellow oil; ¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.11 (1H, dt, J 8.0, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.56 (1H, d, J 6.0 Hz, NH), 7.50 (1H, dd, J 8.0, 2.0 Hz, pyH-3), 6.95 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.47 (0.5H, m, 0.5H of pipH-3), 4.31 (2.5H, m, 0.5H of pipH-3, pipH-4, 1H of pipH-2) 4.00 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, OCH₃), 3.84 (1H, m, 1H of pipH-6), 3.53 (1H, m, BzpipH-4), 3.23 (1H, m, 1H of pipH-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.90 (2H, m, 1H of pipH-2, 1H of BzpipH-2, H-6), 2.08-1.92 (2H, m, 2H of pipH-5, BzpipH-3, H-5), 1.91-1.80 (4H, m, 4H of pipH-5, BzpipH-3, H-5), 1.47 (9H, s, C(CH₃)₃); ¹⁹F nmr (CDCl₃) δ −189.3 (d, J 47.5 Hz); m/z: 569 [M+H]⁺.

Deprotection of the tert-Butyloxycarbonyl Group

To a solution of the tert-butyloxycarbonylpiperidine (1.41 g, 2.48 mmol, 1.0 eq) in dichloromethane (25 mL) was added hydrogen chloride (2.5 mL of a 4.0M solution in dioxane, 9.93 mmol, 4.0 eq). The reaction was stirred at room temperature for 6 hours. A residue formed over the course of the reaction. Et₂O (100 mL) was added resulting in a percipitate after sonication, which was isolated by filtration. The resulting solid was dried under vacuum to yield the fluoropiperidine dihydrochloride as a pale orange solid (1.32 g, quantitative), which was used without further purification; ¹H nmr (D₆-DMSO) δ 8.96 (2H, m, CONH, pyH-6), 8.30 (1H, dt, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.62 (1H, dd, J 8.0 Hz, pyH-3), 6.99 (2H, d, J 9.5 Hz, 2H of C₆₄OCH₃), 4.93, 4.75 (1H, 2m, pipH-3), 4.46 (1H, m, 1H of BzpipH-2, H-6), 4.32 (1H, m, pipH-4), 3.78 (3H, s, OCH₃), 3.69 (1H, m, BzpipH-4), 3.57-3.50 (2H, m, 1H of pipH-2, 1H of BzpipH-2, H-6), 3.28-3.10 (3H, m, 1H of pipH-2, 1H of pipH-6, 1H of BzpipH-2, H-6), 3.08-2.94 (2H, m, 1H of pipH-6, 1H of BzpipH-2, H-6), 2.02 (1H, m, 1H of pipH-5), 1.82 (2H, m, 1H of pipH-5, 1H of BzpipH-3, H-5), 1.63 (1H, m, 1H of BzpipH-3, H-5), 1.55-1.47 (2H, m, 2H of BzpipH-3, H-5); ¹⁹F nmr (D₆-DMSO) δ −188.6 (d, J 50.0 Hz); m/z: 469 [M+H]⁺.

Compound 349

To a suspension of the fluoropiperidine dihydrochloride (0.250 g, 0.462 mmol, 1.0 eq) in dichlormethane (5.0 mL) was added diisopropylethylamine (0.28 mL, 1.617 mmol, 3.5 eq) to form a clear solution, 4-Cyanobenzyl bromide (0.100 g, 0.508 mmol, 1.1 eq) was added and the reaction stirred at room temperature for 5 hours before pouring into NaHCO₃ (40 mL). The organics were extracted with CH₂Cl₂ (3×40 mL), combined, dried (Na₂SO₄) and concentrated under reduced pressure. MPLC (3→5% MeOH—CH₂Cl₂) yielded the cyanobenzylpiperidine (0.162 g, 60%) as a white foam; IR (film) 3313, 2953, 1662, 1622, 1599, 1544, 1448, 1259, 1170, 1027, 971, 912, 848, 731 cm⁻¹; ¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.60 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.48 (1H, d, J 8.0 Hz, pyH-3), 7.43 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.33 (1H, m, NH), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.70, 4.53 (1H, m, pipH-3), 4.15 (1H, m, pipH-4), 3.88 (3H, s, OCH₃), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.63 (2H, s, CH ₂C₆H₄CN), 3.54 (1H, m, BzpipH-4), 3.28-3.09 (3H, m, 2H of BzpipH-2, H-6, 1H of pipH-6), 2.80 (1H, m, 1H of pipH-2), 2.30-2.17 (3H, m, 1H of pipH-6, 1H of pipH-5, 1H of pipH-2), 2.03 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.82 (3H, m, 3H of BzpipH-3, H-5), 1.67 (1H, m, 1H of pipH-5); ¹³C nmr (CDCl₃) δ 199.9, 167.2, 165.3, 163.7, 155.8, 147.5, 143.8, 136.1, 132.2, 130.8, 130.6, 129.2, 128.5, 122.6, 118.8, 114.0, 111.1, 89.5 (90.7, 88.4, d, J 178.5 Hz), 61.7, 56.5 (56.7, 56.3, J 25.0 Hz), 55.5, 52.3 (52.4, 52.1, J 17.5 Hz), 51.7, 46.7, 42.6, 41.9, 29.9 (29.9, 29.8 J 6.5 Hz), 28.6 (28.8, 28.4, J 28.0 Hz); ¹⁹F nmr (CDCl₃) δ −188.5 (d, J=55 Hz); m/z: 584 [M+H]⁺ (found [M+H]⁺, 584.2711, C₃H₃₄FN₅O₄ requires [M+H]⁺ 584.2668).

Compound 350

To a suspension of the fluoropiperidine dihydrochloride (0.100 g, 0.185 mmol, 1.0 eq) in dichloromethane (2.0 mL) was added diisopropylethylamine (0.112 mL, 0.647 mmol, 3.5 eq) forming a clear solution. Trifluoromethoxybenzyl bromide (0.035 mL, 0.218 mmol, 1.2 eq) was added and the reaction stirred at room temperature for 4 hours before pouring into NaHCO₃ (50 mL). The organics were extracted with CH₂Cl₂ (3×45 mL), combined, dried (Na₂SO₄), and concentrated under reduced pressure. MPLC (0-410% MeOH—CH₂Cl₂) yielded the trifluoromethoxypiperidine (0.076 g, 64%) as a white foam; IR (film) 3314, 3074, 2953, 1665, 1623, 1600, 1509, 1449, 1260, 1221, 1169, 1028, 971, 732 cm⁻¹; ¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.48 (1H, d, J 8.5H, pyH-3), 7.33 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 7.15 (2H, d, J 8.0 Hz, 2H of C₆H₄OCF₃), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.69, 4.52 (1H, m, pipH-3), 4.15 (1H, m, pipH-4), 3.87 (3H, s, OCH₃), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.58-3.50 (3H, m, CH ₂C₆H₄OCF₃, BzpipH-4), 3.28-3.08 (3H, m, 2H of BzpipH-2, H-6, 1H of pipH-2 or H-6), 2.82 (1H, m, 1H of pipH-2 or H-6), 2.26-2.14 (3H, m, 1H of pipH-5, 2H of pipH-2, H-6), 2.01 (1H, m, 1H of BzpipH-3, H-5), 1.94-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.66 (1H, m, 1H of pipH-5); ¹³C nmr (CDCl₃) δ 200.0, 167.2, 165.3, 163.7, 155.8, 148.4, 147.4, 136.7, 136.1, 130.8, 130.0, 128.5, 122.7, 120.9, 114.0, 89.7 (90.9, 88.6 J 178.5 Hz), 61.4, 56.3 (56.5, 56.2 J 25.4 Hz), 55.5, 52.4 (52.5, 52.3 J 18.2 Hz), 51.6, 46.7, 42.6, 41.9, 29.9 (30.0, 29.9 J 6.6 Hz), 28.6 (28.8, 28.4 J 17.7 Hz); ¹⁹F nmr (CDCl₃) δ −57.9, −188.4; m/z: 644 [M+H]⁺ (found [M+H]⁺, 643.2534, C₃H₃₄F₄N₄O₅ requires [M+H]⁺ 643.2538).

Compound 349: N-((trans)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-4), 8.07 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.60 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.48 (1H, d, J 8.0 Hz, pyH-3), 7.43 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.33 (1H, m, NH), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.70, 4.53 (1H, m, pipH-3), 4.15 (1H, m, pipH-4), 3.88 (3H, s, OCH₃), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.63 (2H, s, CH ₂C₆H₄CN), 3.54 (1H, m, BzpipH-4), 3.28-3.09 (3H, m, 2H of BzpipH-2, H-6, 1H of pipH-6), 2.80 (1H, m, 1H of pipH-2), 2.30-2.17 (3H, m, 1H of pipH-6, 1H of pipH-5, 1H of pipH-2), 2.03 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.82 (3H, m, 3H of BzpipH-3, H-5), 1.67 (1H, m, 1H of pipH-5); ¹⁹F nmr (CDCl₃) δ −188.5; m/z: 584 [M+H]t.

Compound 350: N-((trans)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.48 (1H, d, J 8.5H, pyH-3), 7.33 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 7.15 (2H, d, J 8.0 Hz, 2H of C₆H₄OCF₃), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.69, 4.52 (1H, m, pipH-3), 4.15 (1H, m, pipH-4), 3.87 (3H, s, OCH₃), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.58-3.50 (3H, m, CH ₂C₆H₄OCF₃, BzpipH-4), 3.28-3.08 (3H, m, 2H of BzpipH-2, H-6, 1H of pipH-2 or H-6), 2.82 (1H, m, 1H of pipH-2 or H-6), 2.26-2.14 (3H, m, 1H of pipH-5, 2H of pipH-2, H-6), 2.01 (1H, m, 1H of BzpipH-3, H-5), 1.94-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.66 (1H, m, 1H of pipH-5); ¹⁹F nmr (CDCl₃) δ −57.9, −188.4; m/z: 644 [M+H]⁺.]

Compound 351: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-cyanophenoxy)piperidin-1-yl)pyridazine-3-carboxamide

¹H nmr (CDCl₃) δ 8.01 (1H, d, J 9.0 Hz, pzH-4 or H-5), 7.86 (1H, d, J 8.5 Hz, NH), 7.62 (2H, d, J 8.0 Hz, 2H of OC₆H₄CN), 7.61 (2H, d, J 9.0 Hz, 2H of CH₂C₆ H ₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of CH₂C₆H₄CN), 7.02 (1H, d, J 10.0 Hz, pzH-4 or H-5), 6.97 (2H, d, J 9.0 Hz, 2H of OC₆H₄CN), 4.72 (1H, m, PhOpipH-4), 3.98 (3H, m, 2H of PhOpipH-2, H-6, pipH-4), 3.86-3.78 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH ₂C₆H₄CN), 2.80 (2H, m, 2H of pipH-2, H-6), 2.22 (dd, J 11.0, 9.0 Hz, 2H of pipH-2, H-6), 2.13-1.93 (6H, m, PhOpipH-3, H-5, 2H of pipH-3, H-5), 1.61 (1H, m, pipH-5); m/z: 522 [M+H]⁺.

Compound 352: N-((trans)-3-fluoro-1-(4-(pyrrolidin-1-yl)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.89 (1H, m, pyH-6), 8.09 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 7.52 (1H, d, J 8.0 Hz, pyH-3), 7.13 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.03 (1H, d, J 8.0 Hz, NH), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.51 (2H, d, J 9.0 Hz, 2H of CsH₄N), 4.68 (1H, m, 1H of BzpipH-2, H-6), 4.65, 4.48 (1H, m, pipH-3), 4.13 (1H, m, pipH-4), 3.87 (4H, m, OCH₃, 1H of BzpipH-2, H-6), 3.54-3.47 (3H, m, NCH ₂C₆H₄N, BzpipH-4), 3.26 (6H, m, 4H of pyrrolidine, 1H of BzpipH-2, H-6, 1H of pipH-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.84 (1H, d, J 11.5 Hz, 1H of pipH-2), 2.19-2.12 (3H, m, 1H of pipH-2, H-5, H-6), 2.08-1.97 (5H, m, 4H of pyrrolidine, 1H of BzpipH-3, H-5), 2.94-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.61 (1H, 1H of pipH-5); ¹⁹F nmr (CDCl₃) δ −188.4; m/z: 528 [M+H]⁺.

Compound 353: N-((trans)-3-fluoro-1-(4-isopropoxybenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.88 (1H, m, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.50 (1H, d, J 8.0 Hz, pyH-3), 7.18 (2H, d, J 8.5 Hz, 2H of C₆H₄OiPr), 7.15 (1H, m, NH), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.83 (2H, d, J 8.5 Hz, 2H of C₆H₄OiPr), 4.67 (1H, m, 1H of BzpipH-2, H-6), 4.67, 4.50 (1H, m, pipH-3), 4.52 (1H, m, OCH(CH₃)₂), 4.03 (1H, m, pipH-4), 3.87 (3H, s, OCH₃), 3.83 (1H, m, 1H of BzpipH-2, H-6), 3.54, 3.47 (2H, d AB system, J 13.0 Hz, CH ₂C₆H₄O), 3.52 (1H, m, BzpipH-4), 3.22 (2H, m, 1H of BzpipH-2, H-6, 1H of pipH-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.83 (1H, d, J 11.0 Hz, 1H of pipH-2), 2.21-2.10 (3H, 1H of pipH-2, H-5, H-6), 2.02 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.76 (3H, m, 3H of BzpipH-3, H-5), 1.63 (1H, m, 1H of pipH-5); ¹⁹F nmr (CDCl₃) δ −188.4; m/z: 617 [M+H]⁺.

Compound 354: N-((trans)-1-(4-cyano-3-fluorobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.88 (1H, m, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 7.57 (1H, dd, J 7.5, 6.5 Hz, 1H of C₆H₃FCN), 7.49 (1H, d, J 8.0 Hz, pyH-3), 7.30 (1H, d, J 7.0 Hz, NH), 7.23 (2H, m, 2H of C₆H₃FCN), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.71 (1H, m, 1H of BzpipH-2, H-6), 4.71, 4.54 (1H, m, pipH-3), 4.17 (1H, m, pipH-4), 3.88 (3H, s, OCH₃), 3.83 (1H, m, 1H of BzpipH-2, H-6), 3.63 (2H, s, CH₂C₆H₃FCN), 3.54 (1H, m, BzpipH-4), 3.28-3.09 (3H, 2H of BzpipH-2, H-6, 1H of pipH-2, H-6), 2.80 (1H, m, 1H of pipH-2, H-6), 2.33-2.17 (3H, m, pipH-2, H-3, H-6), 2.03 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.81 (3H, m, 3H of BzpipH-3, H-5), 1.68 (1H, m, pipH-5); ¹⁹F nmr (CDCl₃) δ −106.6, −188.5; m/z: 602 [M+H]⁺ (found [M+H]⁺, 602.2589, C₃₃H₃₃F₂N₅O₄ requires [M+H]⁺ 602.2813).

Compound 355: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(oxazol-4-ylmethyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.86 (1H, d, J 1.0 Hz, 1H of oxazole), 7.61-7.26 (3H, m, 2H of C₆H₄CN, 1H of oxazole), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.18 (1H, d, J 7.5 Hz, NH), 4.70 (1H, m, PhOpipH-4), 4.02 (1H, m, pipH-4), 3.91 (2H, m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.53 (2H, s, CH₂oxazole), 3.50 (1H, m, 1H of PhOpipH-2, H-6), 2.96 (2H, m, 2H of pipH-2, H-6), 2.26 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.07-1.99 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.88 (1H, m, 1H of PhOpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); m/z: 516 [M+H]⁺.

Compound 356: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(thiazol-2-ylmethyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.71 (1H, dd, J 6.5, 2.0 Hz, 1H of thiophene), 7.58 (3H, m, pyH-3, 2H of C₆H₄CN), 7.27 (1H, dd, J 6.5, 3.5 Hz, 1H of thiophene), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.56 (1H, d, J 7.5 Hz, NH), 4.70 (1H, m, PhOpipH-4), 4.05-3.91 (3H, m, pipH-4, 2H of PhOpipH-2, H-6), 3.89 (2H, s, CH₂thiophene), 3.69 (1H, m, 1H of PhOpipH-2, H-6), 3.52 (1H, m, 1H of PhOpipH-2, H-6), 2.97 (2H, m, 2H of pipH-2, H-6), 2.37 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.04 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.87 (1H, m, 1H of PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m/z: 531 [M+H]⁺.

Compound 357: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(dimethylcarbamoyl)phenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, d, J 8.0 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of 2H of C₆H₄CN), 7.47 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.40 (2H, d, J 9.0 Hz, 2H of C₆H₄CON(CH₃)₂), 6.91 (2H, d, J 9.0 Hz, 2H of C₆H₄CON(CH₃)₂), 4.66 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH₂C₆H₄CN), 3.38 (1H, m, 1H of PhOpipH-2, H-6), 3.05 (6H, s, N(CH₃)₂), 2.82 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, dd, J 10.5, 10.0 Hz, 2H of pipH-2, H-6), 2.20 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.87 (2H, m, 2H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 595 [M+H]⁺.

Compound 358: 5-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

¹H nmr (CDCl₃) δ 8.61 (1H, d, J 2.0 Hz, pyH-6), 8.25 (1H, d, J 8.5 Hz, pyH-3), 7.94 (2H, d, J 9.5 Hz, 2H of C₆H₄COCH₃), 7.90 (1H, m, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.95 (2H, d, J 8.5 Hz, 2H of C₆H₄COCH₃), 4.73 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 4.00-76 (2H, m, 2H of PhOpipH-2, H-6), 3.63 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH ₂C₆H₄CN), 3.40 (1H, m, 1H of PhOpipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.55 (3H, s, COCH₃), 2.23 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.04-1.91 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 566 [M+H]⁺.

Compound 359: 5-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 9.89 (1H, s, NH), 8.68 (1H, d, J 2.0 Hz, pyH-6), 8.41 (1H, 2.5 Hz, N, O-pyH-6), 8.34 (2H, m, pyH-3, N, O-pyH-4), 7.96 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄COCH₃), 7.09 (4H, m, C₆H₄F), 6.95 (3H, m, 2H of C₆H₄COCH₃, N, O-pyH-3), 4.75 (1H, m, PhOpipH-4), 3.98 (1H, m, 1H of PhOpipH-2, H-6), 3.87 (1H, m, 1H of PhOpipH-2, H-6), 3.68 (1H, m, 1H of PhOpipH-2, H-6), 3.42 (1H, m, 1H of PhOpipH-2, H-6), 2.56 (3H, s, COCH₃), 2.04-1.93 (4H, m, PhOpipH-3, H-5); m/z: 555 [M+H]⁺.

Compound 360: 5-(4-(4-(dimethylcarbamoyl)phenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide

¹H nmr (CDCl₃) δ 8.90 (1H, s, NH), 8.69 (1H, m, pyH-6), 8.41 (1H, d, J 3.0 Hz, N, O-pyH-6), 8.35 (2H, m, pyH-3, N, O-pyH-4), 7.96 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.40 (2H, d, J 9.0 Hz, 2H of C₆H₄CON(CH₃)₂), 7.10 (4H, m, C₆H₄F), 6.97 (1H, d, J 9.0 Hz, N, O-pyH-3), 6.92 (2H, d, J 9.0 Hz, 2H of C₆H₄CON(CH₃)₂), 4.68 (1H, m, PhOpipH-4), 3.95 (1H, m, 2H of PhOpipH-2, H-6), 3.89 (1H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 2H of PhOpipH-2, H-6), 3.41 (1H, m, 2H of PhOpipH-2, H-6), 3.06 (6H, s, N(CH₃)₂), 2.02 (2H, m, 2H of PhOpipH-3, H-5), 1.91 (2H, m, 2H of PhOpipH-3, H-5; ¹⁹F nmr (CDCl₃) δ −118.5; m/z: 584 [M+H]⁺.

Compound 361: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazine-3-carboxamide

¹H nmr (CDCl₃) δ 8.00 (1H, d, J 9.5 Hz, pyH-4 or H-5), 7.87 (1H, d, J 8.0 Hz, NH), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.56 (2H, d, J 9.0 Hz, 2H of C₆H₄CF₃), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.01 (2H, d, J 8.5 Hz, pyH-4 or H-5), 7.00 (2H, d, J 9.0 Hz, 2H of C₆H₄CF₃), 4.71 (1H, m, PhOpipH-4), 4.03-3.94 (3H, m, pipH-4, 2H of PhOpipH-2, H-6), 3.86-3.78 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH₂C₆H₄CN), 2.79 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.12-1.93 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −61.6; m/z: 565 [M+H]⁺ (found [M+H]⁺, 565.2567, C₃₀H₃₁F₃N₆O₂ requires [M+H]⁺ 565.2533).

Compound 362: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidin-1-yl)pyridazine-3-carboxamide

¹H nmr (CDCl₃) δ 7.99 (1H, d, J 9.5 Hz, pyH-4 or H-5), 7.96 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.87 (1H, d, J 8.5 Hz, NH), 7.61 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.00 (1H, m, pyH-4 or H-5), 6.97 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.52 (2H, m, 2H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.89 (3H, s, OCH₃), 3.58 (1H, m, BzpipH-4), 3.55 (2H, s. CH₂C₆H₄CN), 3.28 (2H, m, 2H of BzpipH-2, H-6), 2.79 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 9.0 Hz, 2H of pipH-2, H-6), 2.03-1.87 (6H, m, 2H of pipH-3, H-5, BzpipH-3, H-5) 1.63 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −61.6, −114.9; m/z: 539 [M+H]⁺ (found [M+H]⁺, 539.2782, C₃₁H₃₄N₆O₃ requires [M+H]⁺ 539.2765).

Compound 363: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-nitrophenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.20 (2H, d, J 9.0 Hz, 2H of C₆H₄NO₂), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.60 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.44 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.97 (2H, d, J 9.5 Hz, 2H of C₆H₄NO₂), 6.44 (1H, d, J 8.0 Hz, NH), 4.75 (1H, heptet, J 3.0 Hz, PhOpipH-3), 4.00 (1H, m, pipH-4), 3.92 (2H, m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.51 (1H, m, 1H of PhOpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.20 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.12-2.00 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.90 (1H, m, 1H of PhOpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); m/z: 569 [M+H]⁺.

Compound 364: 6-(4-(4-aminophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CD₃OD) δ 8.90 (1H, m, pyH-6), 8.33 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.80 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.70 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.67 (1H, d, J 9.0 Hz, pyH-3), 6.84 (4H, s, C₆ H ₄NH₂), 4.53 (1H, m, PhOpipH-4), 4.15 (2H, s, CH ₂C₆H₄NH₂), 4.10 (1H, m, 1H of PhOpipH-2, H-6), 3.97 (1H, m, 1H of PhOpipH-2, H-6), 3.77 (1H, m, 1H of PhOpipH-2, H-6), 3.63 (1H, m, 1H of PhOpipH-2, H-6), 3.37 (2H, m, 2H of pipH-2, H-6), 2.86 (2H, dd, J 11.5, 12.0 Hz, 2H of pipH-2, H-6), 2.13 (2H, m, 2H of PhOpipH-3, H-5 or pipH-3, H-5), 2.04-1.73 (6H, m, 2H or 4H of pipH-3, H-5, 2H or 4H of PhOpipH-3, H-5); m/z: 539 [M+H]⁺.

Compound 365: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3), 7.94 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.86 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, C₆H₄CN), 6.53 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 4.66 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.73 (1H, m, 1H of BzpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.51 (1H, m, BzpipH-4), 3.37 (4H, m, 4H of pyrrolidine), 3.21-3.13 (2H, m, 2H of BzpipH-2, H-6), 2.80 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.5, 9.5 Hz, pipH-2, H-6), 2.06-2.00 (7H, m, 4H of pyrrolidine, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.91-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 605 [M+H]⁺.

Compound 366: 6-(4-(4-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.5 Hz, pyH-4), 7.63 (1H, m, pyH-3), 7.60 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.39 (2H, d, J 9.0 Hz, 2H of C₆H₄NHAc), 7.15 (1H, s, NHAc), 6.88 (2H, d, J 9.0 Hz, 2H of C₆H₄NHAc), 6.31 (1H, d, J 8.5 Hz, NHCO), 4.56 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.70 (1H, m, 1H of PhOpipH-2, H-6), 3.58 (2H, s, CH ₂C₆H₄CN), 3.48-3.42 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.5, 9.0 Hz, 2H of pipH-2, H-6), 2.15 (3H, s, COCH₃), 2.08-1.92 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m/z: 581 [M+H]⁺.

Compound 367: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonamido)phenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.64 (1H, d, J 8.5 Hz, pyH-3), 7.60 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.20 (2H, d, J 9.0 Hz, 2H of C₆H₄NHMs), 6.90 (2H, d, J 9.0 Hz, C₆H₄NHMs), 6.31 (1H, d, J 8.5 Hz, NHCO), 4.78 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.46 (1H, m, 1H of PhOpipH-2, H-6), 2.96 (3H, s, SO₂CH₃), 2.83 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.06-1.94 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.85 (1H, m, 1H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); m/z: 617 [M+H]⁺.

Compound 412: 6-(4-(3-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.89 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.62 (1H, d, J 7.5 Hz, pyH-3), 7.35 (2H, m, NHAc, C₆H₄NHAcH-2), 7.22 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.19 (1H, t, J 8.0 Hz, C₆H₄NHAcH-5), 6.89 (1H, m, C₆H₄NHAcH-4 or H-6), 6.85 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 6.66 (1H, dd, J 8.0, 1.5 Hz, C₆H₄NHAcH-4 or H-6), 6.29 (1H, d, J 8.0 Hz, NH), 4.60 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.80 (3H, s, OCH₃), 3.69 (1H, m, 1H of PhOpipH-2, H-6), 3.48 (2H, s, CH ₂C₆HOOCH₃), 3.41 (1H, m, 1H of PhOpipH-2, H-6), 2.86 (2H, m, 2H of pipH-2, H-6), 2.15 (5H, m, NHCOCH ₃, 2H of pipH-2, H-6), 2.03-1.92 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.84 (1H, m, 1H of PhOpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5); m/z: 587 [M+H]⁺.

Compound 413: 6-(4-(3-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.89 (1H, m, pyH-6), 8.10 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.56 (1H, d, J 8.0 Hz, pyH-3), 7.54 (1H, br s, C₆H₄NHAcH-2), 7.36 (1H, s, NHAc), 7.29-7.25 (2H, m, 2H of C₆H₄F), 7.18 (1H, t, J 8.5 Hz, C₆H₄NHAcH-5), 6.99 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.90 (1H, d, J 8.5 Hz, C₆H₄NHAcH-4 or H-6), 6.65 (1H, dd, J 8.5, 2.0 Hz, C₆H₄NHAcH-4 or H-6), 6.58 (1H, d, J 7.5 Hz, NH), 4.59 (1H, m, PhOpipH-4), 4.00 (1H, m, pipH-4), 3.87 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 1H of PhOpipH-2, H-6), 3.47 (1H, s, CH ₂C₆H₄F), 3.43 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.14 (5H, m, NHCOCH ₃, 2H of pipH-2, H-6), 2.02-1.90 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.83 (1H, m, 1H of PhOpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −115.8; m/z: 574 [M+H]⁺.

Compound 414: 6-(4-(3-acetamidophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide

¹H nmr (CDCl₃) δ 9.85 (1H, s, NH), 8.93 (1H, d, J 1.5 Hz, pyH-6), 8.45 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.30 (1H, dd, J 8.5, 2.5 Hz, N, O-pyH-4), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4) 7.66 (1H, s, NHAc), 7.39 (1H, d, J 8.5 Hz, pyH-3), 7.34 (1H, br s, C₆H₄NHAcH-2), 7.17 (1H, t, J 8.0 Hz, C₆H₄NHAcH-5), 7.09-7.06 (4H, m, C₆H₄F), 6.90 (2H, m, C₆H₄NHAcH-4 or H-6, N, O-pyH-3), 6.64 (1H, d, J 8.0 Hz, C₆H₄NHAcH-4 or H-6), 4.56 (1H, m, PhOpipH-4), 3.93-3.77 (2H, m, 2H of PhOpipH-2, H-6), 3.59 (1H, m, 1H of PhOpipH-2, H-6), 3.33 (1H, m, 1H of PhOpipH-2, H-6), 2.13 (3H, s, NHCOCH ₃), 1.95-1.89 (3H, m, 3H of PhOpipH-3, H-5), 1.82 (1H, m, 1H of PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −118.5; m/z: 570 [M+H]⁺.

Compound 415: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.87 (1H, s, pyH-4 or pyH-6), 8.08 (1H, s, pyH-4 or pyH-6), 7.93 (2H, d, 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.60 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.95 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 6.64 (1H, m, 1×NH), 4.94 (1H, m, 1×NH), 7.72 (1H, m, 1H of BzpipH-2, H-6), 4.05 (1H, m, pipH-4), 3.88 (3H, s, OCH₃), 3.56 (2H, s. CH ₂C₆H₄CN), 3.56-3.41 (3H, m, BzpipH-4, 1H of BzpipH-2, H-6), 3.13 (4H, m, 2H of BzpipH-2, H-6, CH₂CH₂CH ₂NHCO), 2.83 (2H, m, 2H of pipH-2, H-6), 2.71 (2H, dd, J 7.0, 6.5 Hz, CH ₂CH₂CH₂NHCO), 2.20 (2H, dd, J 12.0, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.89 (2H, m, CH₂CH ₂CH₂NHCO), 1.76 (2H, m, 2H of BzpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5), 1.46 (9H, s, C(CH₃)₃); ¹⁹F nmr (CDCl₃) δ −78.7; m/z: 656 [M+H]⁺.

Compound 416: tert-butyl 3-(5-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-2-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)pyridin-3-yl)propylcarbamate

¹H nmr (CDCl₃) δ 8.87 (1H, s, pyH-4 or H-6), 8.08 (1H, s, pyH-4 or H-6), 7.93 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.60 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.64 (1H, m, NH), 4.94 (1H, m, NHCOOC(CH₃)₃), 4.71 (1H, m, 1H of BzpipH-2, H-6), 4.04 (1H, m, pipH-4), 3.88 (3H, s, OCH₃), 3.56 (2H, s. CH ₂C₆H₄CN), 3.52-3.41 (2H, m, BzpipH-4, 1H of BzpipH-2, H-6), 3.17-3.08 (4H, m, 2H of BzpipH-2, H-6, CH₂CH₂CH ₂NHCO), 2.83 (2H, m, 2H of pipH-2, H-6), 2.71 (2H, dd, J 7.0, 6.5 Hz, CHH₂CH₂CH₂NHCO), 2.20 (2H, dd, J 12.0, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.94-1.82 (3H, m, 1H of BzpipH-3, H-5, CH₂CH ₂CH₂NHCO), 1.76 (2H, m, 2H of BzpipH-3, H-5), 1.67 (2H, m, 2H of pipH3, H-5), 1.46 (9H, s, C(CH₃)₃); m/z: 724 [M+H]⁺, 624 [M+H—CO₂—C₆H₄ ⁺].

Compound 417: N-(1-(4-cyanophenyl)piperidin-4-yl)-6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.86 (1H, d, J 2.0 Hz, pyH-6), 8.05 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.49 (1H, d, J 8.0 Hz, pyH-3), 7.57 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.29-7.24 (2H, m, 2H of C₆H₄F), 7.00 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.87 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.85 (1H, m, NH), 4.23 (1H, m, pipH-4), 3.99 (2H, m, 2H of pipH-2, H-6), 3.75, 3.73 (2H, 2d. AB system, J 5.0 Hz, 2H of piz), 3.48 (2H, s, CH ₂C₆H₄F), 3.46 (2H, m, 2H of piz), 3.07 (2H, t, J 12.0 Hz, 2H of pipH-2, H-6), 2.49, 2.48 (2H, 2d AB system, J 5.0 Hz, 2H of piz), 2.38, 2.37 (2H, 2d AB system, J 5.0 Hz, 2H of piz), 2.13 (2H, m, 2H of pipH-3, H-5), 1.66 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −115.4; m/z: 527 [M+H]⁺.

Compound 418: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanophenyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.09 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.59 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 7.54 (1H, d, J 8.0 Hz, pyH-3), 7.47 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 6.95 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 6.88 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 6.79 (1H, d, J 7.5 Hz, NH), 4.68 (1H, m, PhOpipH-4), 4.25 (1H, m, pipH-4), 3.92-3.81 (4H, m, 2H of pipH-2, H-6, 2H of PhOpipH-2, H-6), 3.67 (1H, m, 1H of PhOpipH-2, H-6), 3.46 (1H, m, 1H of PhOpipH-2, H-6), 3.07 (2H, t, J 12.0 Hz, 2H of pipH-2, H-6), 2.14 (2H, m, 2H of pipH-3, H-5), 2.03-1.94 (3H, m, 3H of PhOpipH-3, H-5), 1.85 (1H, m, 1H of PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m/z: 535 [M+H]⁺.

Compound 419: N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(thiophene-2-carbonyl)piperidine-1-carbonyl)picolinamide

¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3), 7.93 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.75 (1H, dd, J 3.5, 1.0 Hz, thiopheneH-3 or H-5), 7.68 (1H, dd, J 5.0, 1.0 Hz, thiopheneH-3 or H-5), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.16 (1H, dd, J 5.0, 3.5 Hz, thiopheneH-4), 4.68 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.78 (1H, m, 1H of BzpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.41 (1H, m, BzpipH-4), 3.18 (2H, m, 2H of BzpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.01 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.87 (3H, m, 3H of BzpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 542 [M+H]⁺.

Compound 420: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-(methylsulfonyl)phenyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.73 (2H, d, J 9.0 Hz, 2H of C₆H₄CN or C₆ H ₄SO₂CH₃), 7.57 (2H, d, J 9.0 Hz, 2H of C₆H₄CN or C₆ H ₄SO₂CH₃), 7.46 (1H, d, J 8.0 Hz, pyH-3), 7.09 (1H, d, J 8.0 Hz, NH), 6.95 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆ H ₄SO₂CH₃), 6.93 (2H, d, J 9.0 Hz, 2H of C₆H₄CN or C₆ H ₄SO₂CH₃), 4.67 (1H, m, PhOpipH-4), 4.26 (1H, m, pipH-4), 3.93 (2H, m, 2H of pipH-2, H-6), 3.78 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.45-3.37 (1H, m, 1H of PhOpipH-2, H-6), 3.09 (2H, t, J 12.0 Hz, 2H of pipH-2, H-6), 3.00 (3H, s, SO₂CH₃), 2.10 (2H, m, 2H of pipH-3, H-5), 1.98-1.90 (3H, m, 3H of PhOpipH-3, H-5), 1.84 (1H, m, 1H of PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m/z: 588 [M+H]⁺.

Compound 421: 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(4-(methylsulfonyl)phenyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.06 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.73 (2H, d, J 9.0 Hz, 2H of C₆H₄SO₂CH₃), 7.46 (1H, d, J 8.0 Hz, pyH-3), 7.25 (2H, m, 2H of C₆H₄F), 6.99 (3H, m, NH, 2H of C₆H₄F), 6.93 (2H, d, J 9.0 Hz, 2H of C₆ H ₄SO₂CH₃), 4.24 (1H, m, pipH-4), 3.91 (2H, m, 2H of pipH-2, H-6), 3.74, 3.73 (2H, 2d AB system, J 5.0 Hz, 2H of piz), 3.48 (2H, s, CH ₂C₆H₄F), 3.46 (2H, m, 2H of piz), 3.08 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 3.00 (3H, s, SO₂CH₃), 2.50, 2.48 (2H, 2d AB system, J 5.0 Hz, 2H of piz), 2.38, 2.36 (2H, 2d AB system, J 5.0 Hz, 2H of piz), 2.11 (2H, m, 2H of pipH-3, H-5), 1.68 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −115.4; m/z: 581 [M+H]⁺.

Compound 422: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorophenyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.63 (1H, m, pyH-6), 7.85 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.69 (1H, d, J 8.0 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.89 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.55 (2H, m, 2H of C₆H₄F), 4.70 (1H, m, PhOpipH-4), 4.58 (1H, m, pipH-4), 3.91 (2H, m, 2H of pipH-2, H-6 or PhOpipH-2, H-6), 3.78-3.71 (2H, m, 2H of pipH-2, H-6 or PhOpipH-2, H-6), 3.57-3.47 (2H, m, 2H of pipH-2, H-6 or PhOpipH-2, H-6), 3.17 (2H, m, 2H of pipH-2, H-6 or PhOpipH-2, H-6), 2.21-1.94 (7H, 7H of pipH-3, H-5, PhOpipH-3, H-5), 1.88 (1H, m, 1H of pipH-3, H-5, PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −127.1; m/z: 528 [M+H]⁺.

Compound 423: 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxyphenyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.92 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.63 (1H, d, J 8.5 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.92 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 6.84 (2H, d, J 9.5 Hz, 2H of C₆H₄OCH₃), 6.45 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m, PhOpipH-4), 4.12 (1H, m, pipH-4), 3.93-3.84 (2H, m, 2H of pipH-2, H-6, PhOpipH-2, H-6), 3.77 (3H, s, OCH₃), 3.71 (1H, m, 1H of pipH-2, H-6, PhOpipH-2, H-6), 3.53-3.49 (3H, m, 3H of pipH-2, H-6, PhOpipH-3, H-6), 2.85 (2H, t, J 11.5 z, 2H of pipH2, H-6), 2.15 (2H, m, 2H of pipH-3, H-5), 2.06-1.98 (3H, m, 3H of PhOpipH-3, H-5), 1.87 (1H, m, 1H of PhOpipH-3, H-5), 1.74 (2H, m, 2H of pipH-3, H-5); m/z: 540 [M+H]⁺.

Compound 424: 6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 7.65 (1H, d, J 8.0 Hz, pyH-3), 7.33 (1H, t, J 8.0 Hz, C₆H₄OCF₃H-5), 7.24 (2H, m, C₆H₄OCF₃H-2 and H-4 or H-6), 7.10 (1H, d, J 8.5 Hz, C₆H₄OCF₃H-4 or H-6), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.22 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.03 (1H, m, pipH-4), 3.94 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.54 (3H, m, CH ₂C₆H₄OCF₃, BzpipH-4), 3.26 (1H, m, 1H of BzpipH-2, H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.04 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.93-1.81 (3H, m, 3H of BzpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.7; m/z: 625 [M+H]⁺.

Compound 425: 6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(3-methoxybenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.93 (2H, d, J 8.5 Hz, 2H of COC₆H₄OCH₃), 7.57 (1H, d, J 7.5 Hz, pyH-3), 7.22 (1H, t, J 8.0 Hz, C₆H₄OCH₃H-5), 6.95 (2H, d, J 9.0 Hz, 2H of COC₆H₄OCH₃), 6.89 (2H, m, C₆H₄OCH₃H-2 and H-4 or H-6), 6.80 (1H, dd, J 8.5, 2.0 Hz, C₆H₄OCH₃H-4 or H-6), 6.59 (1H, d, J 8.0 Hz, NH), 4.68 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.89 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1×OCH₃), 3.80 (3H, s, 1×OCH₃), 3.53 (2H, s, CH ₂C₆H₄OCH₃), 3.51 (1H, m, BzpipH-4), 3.24 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.10 (1H, m, 1H of BzpipH-2, H-6), 2.91 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.04-2.00 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.91-1.79 (3H, m, 3H of BzpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 571 [M+H]⁺.

426: N-((3S,4R)-3-fluoro-1-((5-methylisoxazol-3-yl)methyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.89 (1H, d, J 2.0 Hz, pyH-6), 8.10 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.53 (1H, d, J 8.0 Hz, pyH-3), 7.09 (1H, d, J 7.5 Hz, NH), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 5.97 (1H, d, J 1.0 Hz, isoxazoleH-4), 4.70-4.62 (1.5H, m, 1H of BzpipH-2, H-6, 0.5H of pipH-3), 4.49 (0.5H, dt, J 5.0, 9.5 Hz, 0.5H of pipH-3), 4.12 (1H, m, pipH-4), 3.87 (3H, s, OCH₃), 3.84 (1H, m, 1H of BzpipH-2, H-6), 3.64 (2H, s, CH ₂isoxazole), 3.53 (1H, m, BzpipH-4), 3.26-20 (2H, m, 1H of pipH-6, 1H of BzpipH-2, H-6), 3.11 (1H, t, J 11.0 Hz, 1H of BzpipH-2, H-6), 2.84 (m, 1H of pipH-2), 2.41 (3H, d, J 1.0 Hz, isoxazoleCH3), 2.32 (1H, m, 1H of pipH-6), 2.27-2.18 (2H, m, 1H of pipH-2, 1H of pipH-5), 2.02 (1H, m, BzpipH-3, H-5), 1.92-1.80 (3H, m, 3H of BzpipH-3, H-5) 1.63 (1H, m, 1H of pipH-5); ¹⁹F nmr (CDCl₃) δ −188.6; m/z: 565 [M+H]⁺.

Compound 427: N-((3S,4R)-3-fluoro-1-((2-methylthiazol-4-yl)methyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.94 (1H, m, pyH-6), 8.16 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.59 (1H, d, J 8.0 Hz, pyH-3), 6.96 (2H, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.95 (1H, s, thiazoleH-4), 4.68 (1H, m, 1H of BzpipH-2, H-6), 4.55 (1H, ddt, J 50.0, 5.0, 9.5 Hz, pipH-3), 4.15 (1H, m, pipH-4), 3.92 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, OCH₃), 3.71, 3.64 (2H, 2d AB system, J 13.0 Hz, CH ₂thiazole), 3.51 (1H, m, BzpipH-4), 3.29-3.20 (2H, m, 1H of pipH-6, 1H of BzpipH-2, H-6), 3.10 (1H, dd, J 12.5, 11.0 Hz, 1H BzpipH-2, H-6), 2.89 (1H, m, 1H of pipH-2), 2.71 (3H, s, thiazoleCH₃), 2.27-2.12 (3H, m, 1H of pipH-2, 1H of pipH-5, 1H of pipH-6), 2.02 (1H, m, 1H of BzpipH-3, H-5), 1.91-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.61 (1H, m, 1H of pipH-5); ¹⁹F nmr (CDCl₃) δ −188.6; m/z: 581 [M+H]⁺.

Compound 428: 6-(4-(4-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.58 (1H, d, J 8.5 Hz, pyH-3), 7.38 (2H, d, J 9.0 Hz, 2H of C₆H₄NHAc), 7.32 (1H, t, J 8.0 Hz, C₆H₄OCF₃H-5), 7.31 (1H, m, 1×NH), 7.23 (2H, m, C₆H₄OCF₃H-2, H-4 or H-6), 7.09 (1H, d, J 8.0 Hz, C₆H₄OCF₃H-4 or H-6), 6.86 (2H, d, J 9.0 Hz, 2H of C₆H₄NHAc), 6.49 (1H, m, 1×NH), 4.54 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.68 (1H, m, 1H of PhOpipH-2, H-6), 3.52 (2H, s, CH ₂C₆H₄OCF₃), 3.47-3.40 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.18 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.14 (3H, s, NHCOCH ₃), 2.04-1.90 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.80 (1H, m, 1H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.7; m/z: 640 [M+H]⁺.

Compound 429: 6-(4-(3-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.89 (1H, m, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.59 (1H, d, J 8.0 Hz, pyH-3), 7.48 (1H, s, 1×NH), 7.36 (1H, s, C₆H₄NHAcH-2), 7.32 (1H, m, C₆H₄NHAcH-5), 7.24-7.16 (3H, m, C₆H₄OCF₃H-2, H-4 or H-6, C₆H₄NHAcH-5), 7.10 (1H, d, J 8.5 Hz, C₆H₄OCF₃H-4 or H-6), 6.90 (1H, d, J 8.0 Hz, C₆H₄NHAcH-4 or H-6), 6.65 (1H, d, J 8.0 Hz, C₆H₄NHAcH-4 or H-6), 6.50 (1H, d, J 8.0 Hz, NH), 4.59 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.67 (1H, m, 1H of PhOpipH-2, H-6), 3.52 (2H, s, CH ₂C₆H₄OCF₃), 3.44 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.18 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.15 (3H, s, NHCOCH ₂), 2.08-1.91 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.81 (1H, m, 1H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.7; m/z: 641 [M+H]⁺.

Compound 430: 6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.81 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C₄ H ₄OCH₃), 7.63 (1H, d, J 8.0 Hz, pyH-3), 7.34 (2H, d, J 9.0 Hz, 2H of C₆H₄OCF₃), 7.15 (2H, d, J 8.0 Hz, 2H of C₆H₄OCF₃), 6.96 (2H, d, J 9.5 Hz, 2H of C₆H₄OCH), 6.26 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.02 (1H, m, pipH-4), 3.94 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.53 (1H, m, BzpipH-4), 3.51 (2H, s, CH ₂C₆H₄OCF₃), 3.25 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.18 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.93-1.73 (4H, m, BzpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.9; m/z: 626 [M+H]⁺.

Compound 431: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) 8.83 (1H, m, pyH-6), 8.05 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.56-7.52 (3H, m, 2H of C₆H₄CN, pyH-3), 7.39-3.37 (4H, m, 2H of C₆H₄CN, 1×NH, C₆H₄NH-2), 7.13 (1H, t, J 8.0 Hz, C₆H₄NH-5), 6.79 (1H, dd, J 8.0, 1.5 Hz, C₆H₄NH-4 or H-6), 6.58 (1H, dd, J 8.0, 2.0 Hz, C₆H₄NH-4 or H-6), 6.26 (1H, d, J 7.5 Hz, 1×NH), 4.55 (1H, m, PhOpipH-4), 3.96 (1H, m, pipH-4), 3.82 (2H, m, 2H of PhOpipH-2, H-6), 3.61 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH ₂C₆H₄CN), 3.42-3.35 (1H, m, 1H of PhOpipH-2, H-6), 2.76 (2H, m, 2H of pipH-2, H-6), 2.14 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 1.99-1.82 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.78 (1H, m, 1H of PhOpipH-3, H-5), 1.54 (2H, m, 2H of pipH-3, H-5), 1.43 (1H, m cPrH-1), 1.01 (2H, m, 2H of cPrH-2, H-3), 0.79 (2H, m, 2H of cPrH-2, H-3); m/z: 608 [M+H]⁺.

Compound 432: 6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.81 (1H, m, pyH-6), 8.03 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.63 (1H, s, 1×NH), 7.50 (1H, d, J 8.5 Hz, pyH-3), 7.36 (1H, s, C₆H₄NH-2), 7.23-7.18 (2H, m, 2H of C₆H₄F), 7.11 (1H, t, J 8.0 Hz, C₆H₄NH-5), 6.92 (2H, t, J 9.0 Hz, 2H of C₆H₄F), 6.82 (1H, dd, J 8.0, 1.0 Hz, C₆H₄NH-4 or H-6), 6.57 (1H, dd, J 8.0, 1.5 Hz, C₆H₄NH-4 or H-6), 6.45 (1H, d, J 8.0 Hz, 1×NH), 4.52 (1H, m, PhOpipH-4), 3.94 (1H, m, pipH-4), 3.80 (2H, m, 2H of PhOpipH-2, H-6), 3.58 (1H, m, 1H of PhOpipH-2, H-6), 3.41 (2H, s, CH ₂C₆H₄F), 3.34 (1H, m, 1H of PhOpipH-2, H-6), 2.77 (2H, m, 2H of pipH-2, H-6), 2.08 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 1.95-1.80 (5H, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.75 (1H, m, 1H of PhOpipH-3, H-5), 1.53 (2H, m, 2H of pipH-3, H-5), 1.45 (1H, m, cPrH-1), 0.99 (2H, m, 2H of cPrH-2, H-3), 0.77 (2H, m, 2H of cPrH-2, H-3); ¹⁹F nmr (CDCl₃) δ −115.9; m/z: 601 [M+H]⁺.

Compound 433: 6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide

¹H nmr (CDCl₃) δ 9.56 (1H, s, 1×NH), 8.85 (1H, m, pyH-6), 8.38 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.24 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.04 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.56 (1H, s, 1×NH), 7.36 (1H, s, C₆H₄NH-2), 7.34 (1H, d, J 8.5 Hz, pyH-3), 7.11 (1H, t, J 8.0 Hz, C₆H₄NH-5), 7.03-6.99 (4H, m, C₆H₄F), 6.86 (1H, d, J 8.5 Hz, N, O-pyH-3), 6.78 (1H, dd, J 8.0, 1.5 Hz, C₆H₄NH-4 or H-6), 6.57 (1H, dd, J 8.0, 2.0 Hz, C₆H₄NH-4 or H-6), 4.52 (1H, m, PhOpipH-4), 3.87 (1H, m, 1H of PhOpipH-2, H-6), 3.74 (1H, m, 1H of PhOpipH-2, H-6), 3.52 (1H, m, 1H of PhOpipH-2, H-6), 3.27 (1H, m, 1H of PhOpipH-2, H-6), 1.91-1.76 (4H, m, PhOpipH-3, H-5), 1.43 (1H, m, cPrH-1), 0.99 (2H, m, 2H of cPrH-2, H-3), 0.789 (2H, m, 2H of cPrH-2, H-3); ¹⁹F nmr (CDCl₃) δ −118.5; m/z: 596 [M+H]⁺.

Compound 434: N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.85 (1H, m, pyH-6), 8.05 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (1H, s, 1×NH), 7.48 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.40 (1H, s, C₆H₄NH-2), 7.11 (1H, t, J 8.0 Hz, C₆H₄NH-5), 6.87 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.80 (1H, dd, J 8.0, 1.0 Hz, C₆H₄NH-4 or H-6), 6.64 (1H, d, J 8.0 Hz, 1×NH), 6.57 (1H, dd, J 8.0, 2.0 Hz, C₆H₄NH-4 or H-6), 4.54 (2H, m, cHexH-1. PhOpipH-4), 4.04 (1H, m, cHexH-4), 3.83 (1H, m, 1H of PhOpipH-2, H-6), 3.77 (1H, m, 1H of PhOpipH-2, H-6), 3.58 (1H, m, 1H of PhOpipH-2, H-6), 3.35 (1H, m, 1H of PhOpipH-2, H-6), 2.04 (2H, m, 2H of cHexH-2, H-6), 1.94-1.80 (4H, m, 4H of cHcxH-2, H-3, H-5, H-6, PhOpipH-3, H-5), 1.80-1.64 (6H, m, 6H of cHexH-2, H-3, H-5, H-6, PhOpipH-3, H-5), 1.45 (1H, m, cPrH-1), 0.99 (2H, m, 2H of cPrH-2, H-3), 0.78 (2H, m, 2H of cPrH-2, H-3); m/z: 609 [M+H]⁺.

Compound 435: 6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl_(h)) δ 8.82 (1H, m, pyH-6), 8.04 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.54 (1H, s, 1×NH), 7.52 (1H, d, J 8.5 Hz, pyH-3), 7.36 (1H, s, C₆H₄NH-2), 7.15 (2H, d, J 8.5 Hz, 2H of C₆ H ₄OCH₃), 7.11 (1H, t, J 8.5 Hz, C₆H₄NH-5), 6.82 (1H, m, C₆H₄NH-4 or H-6), 6.79 (2H, d, J 8.5 Hz, 2H of C₆ H ₄OCH₃), 6.57 (1H, dd, J 8.0, 2.0 Hz, C₆H₄NH-4 or H-6), 6.31 (1H, d, J 7.5 Hz, 1×NH), 4.53 (1H, m, PhOpipH-4), 3.93 (1H, m, pipH-4), 3.81 (2H, m, 2H of PhOpipH-2, H-6), 3.73 (3H, s, OCH₃), 3.59 (1H, m, 1H of PhOpipH-2, H-6), 3.39 (2H, s, CH ₂C₆H₄OCH₃), 3.33 (1H, m, 1H of PhOpipH-2, H-6), 2.79 (2H, m, 2H of pipH-2, H-6), 2.08 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 1.96-1.71 (6H, m, 2H of pipH-3, H-5. PhOpipH-3, H-5), 1.53 (2H, m, 2H of pipH-3, H-5), 1.47-1.39 (1H, m, cPrH-1), 1.00 (2H, m, 2H of cPrH-2, H-3), 0.77 (2H, m, 2H of cPrH-2, H-3); m/z: 613 [M+H]⁺.

Compound 436: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(trifluoromethylthio)phenoxy)piperidine-1-carbonyl)pyridazine-3-carboxamide

¹H nmr (CDCl₃) δ 8.42 (1H, d, J 9.0 Hz, pyH-5 or H-6), 8.07 (1H, d, J 8.0 Hz, NH), 8.01 (1H, d, J 8.5 Hz, pyH-5 or H-6), 7.62 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.58 (2H, d, J 8.5 Hz, 2H of C₆H₄SCF₃), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄SCF₃), 4.71 (1H, m, PhOpipH-4), 4.10-4.03 (2H, m, pipH-4, 1H of PhOpipH-2, H-6), 3.88 (1H, m, 1H of PhOpipH-2, H-6), 3.82 (1H, ddd, J 13.0, 8.5, 4.5 Hz, 1H of PhOpipH-2, H-6), 3.71-3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH ₂C₆H₄CN), 2.84 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.15-1.97 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −43.8; m/z: 625 [M+H]⁺.

Compound 437: 6-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)pyridazine-3-carboxamide

¹H nmr (CDCl₃) δ 8.43 (1H, d, J 8.5 Hz, pyH-5 or H-6), 8.07 (1H, d, J 8.0 Hz, NH), 8.01 (1H, d, J 9.0 Hz, pyH-5 or H-6), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄Ac), 7.62 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.96 (2H, d, J 9.5 Hz, 2H of C₆H₄Ac), 4.78 (1H, m, PhOpipH-4), 4.11-4.04 (2H, m, pipH-4, 1H of PhOpipH-2, H-6), 3.89 (1H, m, 1H of PhOpipH-2, H-6), 3.83 (1H, m, 1H of PhOpipH-2, H-6), 3.72-3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH ₂C₆H₄CN), 2.83 (2H, m, 2H of pipH-2, H-6), 2.56 (3H, s, COCH₃), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.16-2.02 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m/z: 568 [M+H]⁺.

Compound 438: 6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.63 (1H, d, J 8.0 Hz, pyH-3), 7.46 (2H, m, C₆H₄NH-2, 1×NH), 7.34 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₁), 7.19-7.14 (3H, m, 2H of C₆H₄OCF₃, C₆H₄NH-5), 6.86 (1H, d, J 8.5 Hz, C₆H₄NH-4 or H-6), 6.65 (1H, dd, J 8.5, 2.0 Hz, C₆H₄NH-4 or H-6), 6.23 (1H, d, J 8.0 Hz, 1×NH), 4.61 (1H, m, PhOpipH-4), 4.02 (1H, m, pipH-4), 3.95-3.84 (2H, m, 2H of PhOpipH-2, H-6), 3.68 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (2H, s, CH ₂C₆H₄OCF₃), 3.44 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.18 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.05-1.92 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.84 (1H, m, 1H of PhOpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5), 1.49 (1H, m, cPrH-1), 1.08 (2H, m, 2H of cPrH-2, H-3), 0.85 (2H, m, 2H of cPrH-2, H-3); ¹⁹F nmr (CDCl₃) δ −57.9; m/z: 666 [M+H]⁺ (found [M+H]⁺, 666.3879, C₃₅H₃₈F₃N₅O₅ requires [M+H]⁺ 666.2898).

Compound 439: N-(1-(4-methoxybenzyl)piperidin-4-yl)-6-((4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.86 (2H, d, J 8.5 Hz, 2H of C₆H₄N), 7.61 (1H, d, J 8.5 Hz, pyH-3), 7.22 (2H, d, J 8.5 Hz, 2H of C₆₄OCH₃), 6.85 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 6.52 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 6.32 (1H, m, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.90 (1H, m, 1H of BzpipH-2, H-6), 3.79 (3H, s, OCH₃), 3.53 (1H, m, BzpipH-4), 3.49 (2H, s, CH ₂C₆H₄OCH₃), 3.38, 3.35 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.08 (1H, m, 1H of BzpipH-2, H-6), 2.88 (2H, m, 2H of pipH-2, H-6), 2.19 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.05, 2.02 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 1.98 (2H, m, 2H of pipH-3, H-5), 1.91-1.78 (4H, m, BzpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); m/z: 611 [M+H]⁺.

Compound 440: 6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.92 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of CH₄N), 7.56 (1H, d, J 8.5 Hz, pyH-3), 7.34 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 7.14 (2H, d, J 8.0 Hz, 2H of C₆H₄OCF₃), 6.60 (1H, d, J 7.5 Hz, NH), 6.52 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.88 (1H, m, 1H of BzpipH-2, H-6), 3.52 (1H, m, BzpipH-4), 3.50 (2H, s, CH2C6H4OCF3), 3.38, 3.35 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 3.23 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.18 (2H, mdd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.05, 2.03 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 1.98 (2H, m, 2H of pipH-3, H-5), 1.92-1.76 (4H, m, BzpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.9; n/z: 665 [M+H]⁺.

Compound 441: 6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.84 (1H, m, pyH-6), 8.05 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.80 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.49 (1H, d, J 8.0 Hz, pyH-3), 7.25 (1H, t, J 7.5 Hz, C₆H₄OCF₃H-5), 7.17 (2H, m, CH₄OCF₃H-2, H-4 or H-6), 7.02 (1H, d, J 8.0 Hz, C₆H₄OCF₃H-4 or H-6), 6.54 (1H, d, J 8.0 Hz, NH), 6.46 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 4.64 (1H, m, 1H of BzpipH-2, H-6), 3.95 (1H, m, pipH-4), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.46 (2H, s, CH ₂C₆H₄OCF₃), 3.42 (1H, m, BzzpipH-4), 3.31, 3.29 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 3.17 (1H, m, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 2.78 (2H, m, 2H of pipH-2, H-6), 2.12 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 1.99-1.95 (6H, m, 4H of pyrrolidine, 2H of pipH-3, H-5), 1.86-1.72 (4H, m, BzpipH-3, H-5), 1.57 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.7; m/z: 665 [M+H]⁺.

Compound 442: N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.82 (1H, m, pyH-6), 7.86 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.57-7.52 (3H, m, 2H of C₆H₄CN, pyH-3), 6.93 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.77 (1H, d, J 8.0 Hz, NH), 6.53 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.61 (1H, br s, cHexH-1), 4.11 (1H, m, cHexH-4), 3.88 (1H, m, 1H of BzpipH-2, H-6), 3.48 (1H, m BzpipH-4), 3.38, 3.36 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 3.23 (1H, m, 1H of BzpipH-2, H-6), 3.08 (1H, m, 1H of BzpipH-2, H-6), 2.12-2.09 (2H, m, 2H of cHexH-2, H-3, H-5, H-6), 2.05, 2.03 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 1.98-1.90 (2H, m, 2H of cHexH-2, H-3, H-5, H-6, BzpipH-3, H-5), 1.88-1.69 (8H, 8H of cHexH-2, H-3, H-5, H-6, BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −118.6; m/z: 607 [M+H]⁺ (found [M+H]⁺, 606.3158, C₃₆H₃₉N₅O₄ requires [M+H]⁺ 606.3075).

Compound 443: N-(1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.59 (1H, d, J 8.0 Hz, pyH-3), 7.08 (1H, dd, J 12.0, 2.0 Hz, C₆H₃FOCH₃H-2), 6.99 (1H, d, J 8.5 Hz, C₆H₃FOCH₃H-6), 6.89 (1H, t, J 8.5 Hz, C₆H₃FOCH₃H-5), 6.53 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 6.49 (1H, d, J 8.5 Hz, NH), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.89 (1H, m, 1H of BzpipH-32, H-6), 3.87 (3H, s, OCH₃), 3.50 (1H, m, BzpipH-4), 3.43 (2H, s, CH ₂C₆H₃FOCH₃), 3.38, 3.36 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.84 (2H, m, 2H of pipH-2, H-6), 2.15 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.05, 2.03 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 1.99 (2H, m, 2H of pipH-3, H-5), 1.90-1.78 (4H, m, BzpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −135.6; m/z: 629 [M+H]⁺.

Compound 444: 6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1-yl)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of COC₆H₄N), 7.61 (1H, d, J 8.5 Hz, pyH-3), 7.15 (2H, d, J 9.0 Hz, 2H of CH₂C₆H₄N), 6.53 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄N), 6.52 (2H, d, J 8.5 Hz, 2H of 1×C₆H₄N), 6.33 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH-4), 3.90 (1H, m, 1H of BzpipH-2, H-6), 3.49 (1H, m, BzpipH-4), 3.43 (2H, s, CH ₂C₆H₄N), 3.38, 3.35 (4H, 2d AB system, J 6.5 Hz, 4H of 1×pyrrolidine), 3.28, 3.26 (4H, 2d AB system, J 6.5 Hz, 4H of 1×pyrrolidine), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.08 (1H, m, 1H of BzpipH-2, H-6), 2.88 (2H, m, 2H of pipH-2, H-6), 2.14 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.04-1.96 (10H, m, 2H of pipH-3, H-5, 4H of 2×pyrrolidine), 1.90-1.78 (4H, m, BzpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); m/z: 650 [M+H]⁺.

Compound 445: 6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(piperidin-4-yl)nicotinamide (as its dihydrochloride salt)

¹H nmr (CDCl₃) δ 8.99 (1H, s, pyH-6), 8.75 (3H, m, NH, NH₂), 8.30 (1H, dt, J 8.5, 2.0 Hz, pyH-4), 7.98 (2H, d, J 9.0 Hz, C₆H₄OCH₃), 7.65 (1H, d, J 8.0 Hz, pyH-3), 7.04 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 4.50 (1H, m, BzpipH-2, H-6), 4.06 (1H, m, pipH-4), 3.83 (3H, s, OCH₃), 3.73 (1H, m, BzpipH-4), 3.60 (1H, m, 1H of BzpipH-2, H-6), 3.33-3.17 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 3.06-2.98 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 1.99-1.86 (3H, m, 3H of pipH-3, H-5. BzpipH-3, H-5), 1.77-1.65 (3H, m, 3H of pipH-3, H-5, BzpipH-3, H-5), 1.60-1.49 (2H, m, 2H of pipH-3, H-5. BzpipH-3, H-5); m/z: 452 [M+H]⁺.

Compound 446: N-(1-(4-isopropoxybenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) d 8.83 (1H, m, pyH-6), 8.05 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.80 (2H, d, J 9.5 Hz, 2H of C₆H₄N), 7.54 (1H, d, J 8.0, pyH-3), 7.13 (2H, d, J 9.0 Hz, 2H of C₆H₄OiPr), 6.76 (2H, d, J 9.0 Hz, 2H of C₆H₄OiPr), 6.46 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 6.28 (1H, d, J 8.0 Hz, NH), 4.63 (1H, m, 1H of BzpipH-2, H-6), 4.46 (1H, heptet, J 6.0 Hz, OCH(CH₃)₂), 3.94 (1H, m, pipH-4), 3.84 (1H, m, 1H of BzpipH-2, H-6), 3.43 (1H, m, BzpipH-4), 3.39 (2H, s, CH ₂C₆H₄OiPr), 3.31, 3.29 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 3.17 (1H, m, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 2.80 (2H, m, 2H of pipH-2, H-6), 2.09 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 1.98, 1.96 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 1.92 (2H, m, 2H of pipH-3, H-5), 1.87-1.67 (4H, m, 4H of BzpipH-3, H-5), 1.55 (2H, m, 2H of pipH-3, H-5); m/z: 638 [M+H]⁺.

Compound 447: N-(1-(4-cyano-3-fluorobenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.56 (1H, d, J 8.0 Hz, pyH-3), 7.54 (1H, dd, J 8.0, 6.5 Hz, C₆H₃FCNH-H-5 or H-6), 7.26 (1H, d, J 10.0 Hz, C₆H₃FCNH-2), 7.22 (1H, d, J 8.5 Hz, C₆H₃FCNH-5 or H-6), 6.61 (1H, d, J 7.5 Hz, NH), 6.53 (2H, d, J 8.5 Hz, 2H of C₆H₄N), 4.71 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.90 (1H, m, 1H of BzpipH-2, H-6), 3.55 (2H, s, CH2C6H4N), 3.51 (1H, m, BzpipH-4), 3.38, 3.36 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.05, 2.03 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolinine), 2.00 (2H, m, 2H of pipH-3, H-5), 1.95-1.78 (4H, m, BzpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −106.9; m/z: 624 [M+H]⁺.

Compound 448: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(cyclopropanesulfonamido)phenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.45 (1H, m, pyH-6), 8.08 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (1H, d, J 8.5 Hz, pyH-3), 7.54 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.38 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.15 (2H, d, J 9.5 Hz, 2H of C₆ H ₄NHSO₂), 6.82 (2H, d, J 9.0 Hz, 2H of C₆ H ₄NHSO₂), 6.10 (1H, s, NHSO₂), 6.04 (1H, d, J 7.5 Hz, NH), 4.51 (1H, m, PhOpipH-4), 3.97 (1H, m, pipH-4), 3.84 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 1H of PhOpipH-2, H-6), 3.46-3.38 (1H, m, 1H of PhOpipH-2, H-6), 2.76 (2H, m, 2H of pipH-2, H-6), 2.36 (1H, m, cPrH-1), 2.15 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.00-1.1.86 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.79 (1H, m, 1H of PhOpipH-3, H-5), 1.53 (2H, m, 2H of pipH-3, H-5), 1.05 (2H, m, 2H of cPrH-2, H-3), 0.88 (2H, m, 2H of cPrH-2, H-3); m/z: 644 [M+H]⁺.

Compound 449: 6-(4-(4-(cyclopropanesulfonamido)phenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide

¹H nmr (CDCl₃) δ 9.45 (1H, s, 1×NH), 8.95 (1H, m, pyH-6), 8.44 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.33 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.44 (1H, d, J 8.0 Hz, pyH-3), 7.22 (2H, d, J 9.0 Hz, 2H of C₆ H ₄NHSO₂), 7.20-7.08 (4H, m, C₆H₄F), 6.94 (1H, d, J 8.5 Hz, N, O-pyH-3), 6.89 (2H, d, J 9.0 Hz, 2H of C₆ H ₄NHSO₂), 6.29 (1H, s, 1×NH), 4.58 (1H, m, PhOpipH-4), 3.99-3.93 (1H, m, 1H of PhOpipH-2, H-6), 3.88-3.83 (1H, m, 1H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.41-3.36 (1H, m, 1H of PhOpipH-2, H-6), 2.43 (1H, m, cPrH-1), 2.01-1.91 (3H, m, 3H of PhOpipH-3, H-5), 1.84 (1H, m, 1H of PhOpipH-3, H-5), 1.12 (2H, m, 2H of cPrH-2, H-3), 0.94 (2H, m, 2H of cPrH-2, H-3); ¹⁹F nmr (CDCl₃) δ −118.5; m/z: 632 [M+H]⁺.

Compound 450: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, d, J 2.0 Hz, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.96 (2H, d, J 9.5 Hz, 2H of C₆H₄SO₂), 7.70 (1H, d, J 8.5 Hz, pyH-3), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.11 (2H, d, J 9.0 Hz, 2H of C₆H₄SO₂), 6.14 (1H, d, J 7.5 Hz, NH), 4.79 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.94 (2H, m, 2H of PhOpipH-2, H-6), 3.75 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (3H, m, 1H of PhOpipH-2, H-6, CH ₂C₆H₄CN), 2.83 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.14-1.98 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.92 (1H, m, 1H of PhOpipH-3, H-5) 1.62 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −78.8; m/z: 656 [M+H]⁺.

Compound 451: N-((3S,4R)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.96 (2H, d, J 8.5 Hz, 2H of C₆H₄SO₂), 7.64 (1H, d, J 8.5 Hz, pyH-3), 7.62 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.44 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.11 (2H, d, J 9.0 Hz, 2H of C₆H₄SO₂), 6.64 (1H, d, J 7.5 Hz, NH), 4.79 (1H, m, PhOpipH-4), 4.56 (1H, dtd, J 50.5, 9.5, 4.5 Hz, pipH-3), 4.15 (1H, m, pipH-4), 3.99-3.87 (2H, m, 2H of PhOpipH-2, H-6), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 4.14, 4.09 (2H, 2d AB system, J 7.5 Hz, CH2C6H4CN), 3.54 (1H, m, 1H of PhOpipH-2, H-6), 3.18 (1H, m, 1H of pipH-2), 2.80 (1H, m, 1H of pipH-6), 2.13-2.18 (3H, m, 1H of pipH2, 1H of pipH-5, 1H of pipH-6), 2.10 (1H, m, 1H of PhOpipH-3, H-5), 2.04 (2H, m, 2H of PhOpipH-3, H-5), 1.91 (1H, m, 1H of PhOpipH-3, H-5), 1.63 (1H, m, 1H of pipH-5); ¹⁹F nmr (CDCl₃) δ −78.8, −188.6; m/z: 674 [M+H]⁺.

Compound 452: N-((3R,4R)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

Compound 452 was separated from the racemic mixture of Compound 349 using chiral chromatography on an (R,R)-Whelk-O 1 25 cm×10 mm column (silica modified with covalently bound 4-(3,5-dinitrobenzamide)tetrahydrophenanthrene), available from Regis Technologies. The instrument was a TharSFC semi-preparative HPLC system, and elution was performed isocratically using 50% MeOH with 0.1% diethylamine in supercritical carbon dioxide at 14 mL/min at 30° C. Compound 452 was the later-eluting peak (at about 21 minutes under the conditions described above). The spectral data agree with Compound 349. Compound 452 was independently enantioselectively synthesized as described in the following scheme:

The first step of the synthesis followed the method of Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C., J. Am. Chem. Soc., 2011, 133(6), 1738-1741, which is hereby incorporated herein by reference in its entirety, 9-Epi-DHQA is (1R)-((2R)-5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methanamine. The optical rotation [a] of the (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate was −20.0° (c 0.33, CH₂Cl₂); the literature value for the corresponding (3S,4R) compound is +21.60. See International Patent Application Publication no. WO 2010/128425.

Compound 453: N-((3S,4S)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

Compound 453 was separated from the racemic mixture of Compound 349 using chiral chromatography as described above with reference to Compound 452. Compound 452 was the earlier-eluting peak (at about 20 minutes under the conditions described above). The spectral data agree with Compound 349.

Compound 454: N-((cis)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.94 (1H, d, J 2.0 Hz, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.59 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.94 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 6.93 (1H, m, NH), 4.87 (0.5H, m, 0.5H of pipH-3), 4.68 (1.5H, m, 0.5H of pipH-3, 1H of BzpipH-2, H-6), 4.28-4.12 (1H, m, pipH-4), 3.91 (1H, m, 1H of BzpipH-2, H-6), 3.86 (3H, s, OCH3), 3.64, 3.58 (2H, 2d AB system, J 14.0 Hz, CH2C6H4CN), 3.52 (1H, m, BzpipH-4), 3.28-3.16 (2H, m, 1H of pipH-2, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.91 (1H, m, 1H of pipH-6), 2.41 (0.5H, d, J 13.0 Hz, 0.5H of pipH-2), 2.26 (1.5H, m, 0.5H of pipH-2, 1H of pipH-6), 2.10-1.98 (2H, m, 2H of pipH-5, BzpipH-3, H-5), 1.91-1.80 (4H, m, 4H of pipH-5, BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −200.8 (q, J=63 Hz); m/z: 584 [M+H]⁺.

Compound 455: 6-(4-(4-(cyclopropanecarbonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 8.00 (2H, d, J 9.0 Hz, 2H of C₆H₄OCF₃ or C₆H₄COcPr), 7.64 (1H, d, J 8.0 Hz, pyH-3), 7.34 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃ or C₆H₄COcPr), 7.15 (2H, d, J 8.0 Hz, 2H of C₆H₄OCF₃ or C₆H₄COcPr), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄OCF₃ or C₆H₄COcPr), 6.30 (1H, d, J 7.5 Hz, NH), 4.73 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.92 (2H, m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (3H, m, CH ₂C₆H₄OCF₃, 1H of PhOpipH-2, H-6), 2.86 (2H, m, 2H of pipH-2, H-6), 2.62 (1H, tt, J 7.5, 4.5 Hz, cPrH-1), 2.18 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.10-1.92 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.87 (1H, m, 1H of PhOpipH-3, H-5), 1.60 (2H, m, 2H of pipH-3, H-5), 1.21 (2H, m, 2H of cPrH-2, H-3), 1.00 (2H, m, 2H of cPrH-2, H-3); ¹⁹F nmr (CDCl₃) δ −57.2; m/z: 651 [M+H]⁺.

Compound 456: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(cyclopropanecarbonyl)phenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.91 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 8.01 (2H, d, J 9.0 Hz, 2H of C₆H₄COcPr), 7.62 (1H, d, J 7.5 Hz, pyH-3), 7.60 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.97 (2H, d, J 9.0 Hz, 2H of C₆H₄COcPr), 6.40 (1H, d, 8.0 Hz, NH), 4.73 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.96-3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH₂C₆H₄CN), 3.52 (1H, m, 1H of PhOpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.62 (tt, J 7.5, 4.5 Hz, cPrH-1), 2.20 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.05-1.94 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.89 (1H, m, 1H of PhOpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5), 1.21 (2H, m, 2H of cPrH-2, H-3), 1.01 (2H, m, 2H of cPrH-2, H-3); m/z: 593 [M+H]⁺.

Compound 457: 6-(4-(4-(cyclopropanecarbonyl)phenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide

¹H nmr (CDCl₃) δ 9.63 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.46 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.34 (1H, dd, J 8.5, 2.5 Hz, N, O-pyH-4), 8.11 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 8.01 (2H, d, J 9.0 Hz, 2H of C₆H₄COcPr), 7.41 (1H, d, J 8.0 Hz, pyH-3), 7.10-7.07 (4H, m, C₆H₄F), 6.96 (2H, d, J 8.5 Hz, 2H of C₆H₄COcPr), 6.95 (1H, d, J 8.5 Hz, N, O-pyH-3), 4.74 (1H, m, PhOpipH-4), 4.01 (1H, m, 1H of PhOpipH-2, H-6), 3.86 (1H, m, 1H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.41 (1H, m, 1H of PhOpipH-2, H-6), 2.62 (1H, tt, J 8.0, 4.5 Hz, cPrH-1), 2.11-1.94 (3H, m, 3H of PhOpipH-3, H-5), 1.89 (1H, m, 1H of PhOpipH-3, H-5), 1.21 (2H, m, 2H of cPrH-2, H-3), 1.01 (2H, m, 2H of cPrH-2, H-3); ¹⁹F nmr (CDCl₃) δ −118.5; m/z: 581 [M+H]⁺.

Compound 458: 6-(4-(4-(cyclopropanecarbonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 8.00 (2H, d, J 9.0 Hz, 2H of C₆H₄COcPr), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.23 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄COcPr), 6.85 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.38 (1H, d, J 7.5 Hz, NH), 4.73 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.95-3.86 (2H, m, 2H of PhOpipH-2, H-6), 3.79 (3H, s, OCH₃), 3.71 (1H, m, PhOpipH-2, H-6), 3.50 (3H, m, CH₂CH₄OCH₃. 1H of PhOpipH-2, H-6), 2.90 (2H, m, 2H of pipH-2, H-6), 2.62 (1H, tt, J 8.0, 4.5 Hz, cPrH-1), 2.20 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.02 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.88 (1H, m, 1H of PhOpipH-3, H-5), 1.21 (2H, m, 2H of cPrH-2, H-3), 1.01 (2H, m, 2H of cPrH-2, H-3); m/z: 597 [M+H]⁺.

Compound 459: N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 9.64 (1H, s, NH), 8.96 (1H, m, pyH-6), 8.52 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.44 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of C₆ H ₄SO₂CH₃), 7.68 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.44 (1H, d, J 8.0 Hz, pyH-3), 7.23 (2H, d, J 9.5 Hz, 2H of C₆H₄CN), 7.06 (1H, m, N, O-pyH-3), 7.03 (2H, d, J 9.0 Hz, 2H of C₆ H ₄SO₂CH₃), 4.75 (1H, m, PhOpipH-4), 4.02 (1H, m, 1H of PhOpipH-2, H-6), 3.88 (1H, m, 1H of PhOpipH-2, H-6), 3.66 (1H, m, 1H of PhOpipH-2, H-6), 3.45 (1H, m, 1H of PhOpipH-2, H-6), 3.04 (3H, s, SO₂CH₃), 2.18-1.96 (3H, m, 3H of PhOpipH-3, H-5), 1.90 (1H, m, 1H of PhOpipH-3, H-5); m/z: 598 [M+H]⁺.

Compound 460: N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 9.95 (1H, s, NH), 8.93 (1H, d, J 2.0 Hz, pyH-6), 8.57 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.46 (1H, dd, J 8.5, 2.5 Hz, N, O-pyH-4), 8.09 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.67 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.38 (1H, d, J 8.5 Hz, pyH-3), 7.22 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.06 (1H, d, J 8.5 Hz, N, O-pyH-3), 6.96 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 4.70 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.79 (1H, m, 1H of BzpipH-2, H-6), 3.55 (1H, m, BzpipH-4), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.16 (1H, m, 1H of BzpipH-2, H-6), 2.04 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.82 (3H, m, 3H of BzpipH-3, H-5); m/z: 562 [M+H]⁺.

Compound 461: N-((cis)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.96 (1H, m, pyH-6), 8.17 (1H, dd, J 8.0, 2.0m Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.68 (1H, dd, J 8.0, 0.5 Hz, pyH-3), 7.36 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCF₃), 7.17 (2H, d, J 8.0 Hz, 2H of C₆H₄OCF₃), 6.95 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 6.57 (1H, d, J 9.0 Hz, NH), 4.86 (0.5H, m, 0.5H of pipH-3), 4.68 (1.5H, m, 1H of BzpipH-2, H-6, 0.5H of pipH-3), 4.33-4.15 (1H, m, pipH-4), 3.96 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.60, 3.55 (2H, 2d AB system, J 14.0 Hz, CH₂C₆H₄OCF₃), 3.52 (1H, m, BzpipH-4), 3.31-3.22 (2H, m, 1H of pipH-2, 1H of BzpipH-2, H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.95 (1H, m, 1H of pipH-6), 2.39 (0.5H, d, J 12.5 Hz, 0.5H of pipH-2), 2.24 (1.5 Hz, 0.5H of pipH-2, 1H of pipH-6), 2.05-1.97 (2H, m, 1H of pipH-5, 1H of BzpipH-3, H-5), 1.93-1.81 (4H, m, 1H of pipH-5, 3H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.9, −200.8; m/z: 644 [M+H]⁺.

Compound 462: N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 9.98 (1H, s, NH), 8.93 (1H, m, pyH-6), 8.56 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.42 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.10 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.99 (2H, d, J 9.0 Hz, 2H of C₆ H ₄COCH₃), 7.93 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.38 (1H, d, J 8.0 Hz, pyH-3), 7.18 (2H, d, J 8.5 Hz, 2H of C₆ H ₄COCH₃), 7.03 (1H, d, J 9.0 Hz, N, O-pyH-3), 6.95 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.68 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.78 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, BzpipH-4), 3.23 (1H, m, 1H of BzpipH-2, H-6), 3.15 (1H, m, 1H of BzpipH-2, H-6), 2.59 (3H, s, COCH₃), 2.03 (1H, m, 1H of BzpipH-3, H-5), 1.92-1.81 (3H, m, 3H of BzpipH-3, H-5); m/z: 579 [M+H]⁺.

Compound 463: N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 9.99 (1H, s, NH), 8.90 (1H, m, pyH-6), 8.57 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.46 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (1H, dt, J 6.5, 8.5 Hz, C₆H₃F₂H-6), 7.68 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.34 (1H, d, J 8.0 Hz, pyH-3), 7.22 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.05 (1H, d, J 9.0 Hz, N, O-pyH-3), 7.00 (1H, m, C₆H₃F₂H-3 or H-5), 6.89 (1H, ddd, J 11.0, 8.5, 2.5 Hz, C₆H₃F₂H-3 or H-5), 4.67 (1H, m, 1H of BzpipH-2, H-6), 3.75 (1H, m, 1H of BzpipH-2, H-6), 3.42 (1H, m, BzpipH-4), 3.24-3.09 (2H, m, 2H of BzpipH-2, H-6), 2.09 (1H, m, 1H of BzpipH-3, H-5), 1.91-1.72 (3H, m, 3H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.1, −106.5; m/z: 568 [M+H]⁺.

Compound 464: N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 9.62 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.41 (1H, dd, J 8.0, 2.5 Hz, N, O-pyH-4), 8.11 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 8.01 (2H, d, J 9.0 Hz, 2H of C₆ H ₄COCH₃), 7.87 (1H, dt, J 6.5, 8.5 Hz, C₆H₃F₂H-6), 7.42 (1H, d, J 8.0 Hz, pyH-3), 7.19 (2H, d, J 9.0 Hz, 2H of C₆ H ₄COCH₃), 7.04 (1H, d, J 9.0 Hz, N, O-pyH-3), 6.99 (1H, m, C₆H₃F₂H-3 or H-5), 6.89 (1H, ddd, J 11.0, 8.4, 2.0 Hz, C₆H₃F₂H-3 or H-5), 4.67 (1H, m, 1H of BzpipH-2, H-6), 3.79 (1H, m, 1H of BzpipH-2, H-6), 3.41 (1H, m, BzpipH-4), 3.25-3.08 (2H, m, 2H of BzpipH-2, H-6), 2.60 (3H, s, COCH₃), 2.08 (1H, m, 1H of BzpipH-3, H-5), 1.91-1.74 (3H, m, 3H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.3, −106.5; m/z: 585 [M+H]⁺.

Compound 465: 6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(6-(4-(methylsulfonyl)phenoxy)pyridin-3-yl)nicotinamide

¹H nmr (CDCl₃) δ 9.92 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.59 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.45 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.11 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.95 (2H, d, J 8.5 Hz, 2H of C₆ H ₄OCH₃ or C₆ H ₄SO₂CH₃), 7.93 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃ or C₆ H ₄SO₂CH₃), 7.39 (1H, d, J 8.0 Hz, pyH-3), 7.30 (2H, d, J 9.0 Hz, 2H of C₆H₄SO₂CH₃), 7.07 (1H, d, J 9.0 Hz, N, O-pyH-3), 6.96 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.69 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.79 (1H, m, 1H of BzpipH-2, H-6), 3.55 (1H, m, BzpipH-4), 3.29-3.13 (2H, m, 2H of BzpipH-2, H-6), 3.07 (3H, s, SO₂CH₃), 2.03 (1H, m, 1H, m, 1H of BzpipH-3, H-5), 1.93-1.81 (3H, m, 3H of BzpipH-3, H-5); m/z: 615 [M+H]⁺.

Compound 466: 6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-(methylsulfonyl)phenoxy)pyridin-3-yl)nicotinamide

¹H nmr (CDCl₃) δ 10.00 (1H, s, NH), 8.91 (1H, m, pyH-6), 8.60 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.46 (1H, dd, J 8.5, 2.5 Hz, N, O-pyH-4), 8.07 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.96 (2H, d, J 8.5 Hz, 2H of C₆ H ₄SO₂CH₃), 7.87 (1H, dt, J 6.5, 9.0 Hz, C₆H₃F₂H-6), 7.35 (1H, d, J 8.0 Hz, pyH-3), 7.30 (2H, d, J 8.5 Hz, 2H of C₆ H ₄SO₂CH₃), 7.07 (1H, d, J 8.5 Hz, N, O-pyH-3), 6.99 (1H, m, C₆H₃F₂H-3 or H-5), 6.89 (1H, ddd, J 11.0, 8.5, 2.0 Hz, C₆H₃F₂H-3 or H-5), 4.67 (1H, m, 1H of BzpipH-2, H-6), 3.75 (1H, m, 1H of BzpipH-2, H-6), 3.42 (1H, m, BzpipH-4), 3.25-3.09 (2H, m, 2H of BzpipH-2, H-6), 3.07 (3H, s, SO₂CH₃), 2.09 (1H, m, 1H of BzpipH-3, H-5), 1.91-1.75 (3H, m, 3H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.2, −106.5; m/z: 621 [M+H]⁺.

Compound 467: N-(6-(4-fluorophenylsulfonyl)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 10.11 (1H, s, NH), 8.98 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.90 (1H, m, pyH-6), 8.63 (1H, dd, J 8.5, 2.5 Hz, N, O-pyH-4), 8.20 (1H, d, J 8.5 Hz, N, O-pyH-3), 8.10-8.06 (3H, m, pyH-4, 2H of C₆H₄F), 7.94 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.39 (1H, d, J 8.5 Hz, pyH-3), 7.20 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.97 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 4.69 (1H, m, 1H of BzpipH-2, H-6), 3.89 (3H, s, OCH₃), 3.76 (1H, m, 1H of BzpipH-2, H-6), 3.55 (1H, m, BzpipH-4), 3.21 (2H, m, 2H of BzpipH-2, H-6), 2.04 (1H, m, 1H of BzpipH-3, H-5), 1.94-1.76 (3H, m, 3H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −103.6; m/z: 603 [M+H]⁺ (found [M+H]⁺, 603.1692, C₃₁H₂₇FN₄O₆S requires [M+H]⁺ 603.1708).

Compound 468: N-(5-(4-cyanophenoxy)pyridin-2-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 9.32 (1H, s, NH), 8.97 (1H, d, J 2.0 Hz, pyH-6), 8.50 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.41 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.16 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.68 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.50 (1H, d, J 8.0 Hz, pyH-3), 7.23 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.07 (1H, d, J 9.0 Hz, N, O-pyH-3), 6.96 (2H, d, J 8.5 Hz, 2H of C₆ H ₄OCH₃), 4.69 (1H, m, 1H of BzpipH-2, H-6), 3.89 (3H, s, OCH₃), 3.85 (1H, m, 1H of BzpipH-2, H-6), 3.55 (1H, m, BzpipH-4), 3.22-3.10 (2H, m, 2H of BzpipH-2, H-6), 2.02 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.80 (3H, m, 3H of BzpipH-3, H-5); m/z: 562 [M+H]⁺.

Compound 469: N-(5-(4-cyanophenoxy)pyridin-2-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 9.72 (1H, s, NH), 8.93 (1H, m, pyH-6), 8.54 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.44 (1H, dd, J 9.0, 3.0 Hz, N, O-pyH-4), 8.10 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.88 (1H, dt, J 6.5, 9.0 Hz, C₆H₃F₂H-6), 7.68 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.40 (1H, d, J 8.0 Hz, pyH-3), 7.23 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.06 (1H, d, J 9.0 Hz, N, O-pyH-3), 7.00 (1H, m, C₆H₃F₂H-3 or H-5), 6.90 (1H, ddd, J 11.0, 8.5, 2.0 Hz, C₆H₃F₂H-3 or H-5), 4.67 (1H, m, 1H of BzpipH-2, H-6), 3.77 (1H, m, 1H of BzpipH-2, H-6), 3.42 (1H, m, BzpipH-4), 3.25-3.08 (2H, m, 2H of BzpipH-2, H-6), 2.09 (1H, m, 1H of BzpipH-3, H-5), 1.91-1.75 (3H, m, 3H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.2, −106.5; m/z: 568 [M+H]⁺.

Compound 470: 6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.88 (1H, m, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.89 (2H, dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.63 (1H, d, J 7.5 Hz, pyH-3), 7.34 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 7.26 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 7.16 (2H, d, J 7.5 Hz, 2H of C₆H₄OCF₃), 6.31 (1H, d, J 8.0 Hz, NH), 4.83 (1H, m, 1H of BzpipH-2, H-6), 4.13 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.52 (2H, s, CH2C6H4OCF3), 3.16 (1H, tt, J 12.0, 3.5 Hz, BzpipH-4), 3.04 (1H, m, 1H of BzpipH-2. H-6), 2.87-2.75 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 2.17 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.01 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.79 (2H, qd, J 12.5, 4.0 Hz, 2H of BzpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.9, −102.6; m/z: 649 [M+H]⁺.

Compound 471: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.89 (dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.63 (1H, m, pyH-3), 7.61 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.27 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.36 (1H, d, J 7.5 Hz, NH), 4.83 (1H, m, 1H of BzpipH-2, H-6), 4.13 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.56 (2H, s, CH ₂C₆H₄CN), 3.17 (1H, tt, J 12.0, 4.0 Hz, BzpipH-4), 3.04 (1H, t, J 12.0 Hz, 1H of BzpipH-2, H-6), 2.85-2.74 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 2.20 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.11-1.95 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.80 (qd, J 12.5, 4.0 Hz, 2H of BzpipH-3, H-5), 1.60 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −102.6; m/z: 590 [M+H]⁺.

Compound 472: N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 9.61 (1H, s, NH), 8.92 (1H, d, J 2.0 Hz, pyH-6), 8.49 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.42 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.11 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.89 (2H, dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.69 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.44 (1H, d, J 8.0 Hz, pyH-3), 7.27 (2H, m, 2H of C₆H₄F), 7.23 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.06 (1H, d, J 8.5 Hz, N, O-pyH-3), 4.83 (1H, m, 1H of BzpipH-2, H-6), 3.96 (1H, m, 1H of BzpipH-2, H-6), 3.17 (1H, m, BzpipH-4), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.84 (1H, m, 1H of BzpipH-2, H-6), 2.10 (1H, d, J 12.0 Hz, 1H of BzpipH-3, H-5), 1.99 (1H, d, J 11.5 Hz, 1H of BzpipH-3, H-5), 1.82 (2H, m, 2H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −102.2; m/z: 586 [M+H]⁺.

Compound 473: N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 9.31 (1H, s, NH), 8.95 (1H, m, pyH-6), 8.45 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.38 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.14 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 8.02 (2H, d, J 9.0 Hz, 2H of C₆H₄Ac), 7.89 (2H, dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.49 (1H, d, J 8.0 Hz, pyH-3), 7.27 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 7.20 (2H, d, J 9.0 Hz, 2H of C₆H₄Ac), 7.05 (1H, d, J 9.0 Hz, N, O-pyH-3), 4.83 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, 1H of BzpipH-2, H-6), 3.17 (1H, m, BzpipH-4), 3.06 (1H, m, 1H of BzpipH-2, H-6), 2.83 (1H, m, 1H of BzpipH-2, H-6), 2.60 (3H, s, COCH₃), 2.10 (1H, d, J 12.5 Hz, 1H of BzpipH-3, H-5), 2.01 (1H, d, J 12.5 Hz, 1H of BzpipH-3, H-5), 1.82 (2H, qd, J 12.5, 4.0 Hz, 2H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −102.3; m/z: 603 [M+H]⁺ (found [M+H]⁺, 603.1689, C₃₁H₂₇FN₄O₆S requires [M+H]⁺ 603.1708).

Compound 474: 6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.91 (2H, dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.66 (1H, d, J 8.0 Hz, pyH-3), 7.29 (2H, t, J 9.0 Hz, 2H of C₆H₄F), 7.24 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 6.88 (2H, d, J 8.5 Hz, 2H of C₆ H ₄OCH₃), 6.31 (1H, d, J 8.0 Hz, NH), 4.85 (1H, m, 1H of BzpipH-2, H-6), 4.16 (1H, m, 1H of BzpipH-2, H-6), 4.02 (1H, m, pipH-4), 3.83 (3H, s. OCH₃), 3.48 (2H, s, CH ₂C₆H₄OCH₃), 3.19 (1H, tt, J 12.0, 3.5 Hz, BzpipH-4), 3.07 (1H, t, J 12.0 Hz, 1H of BzpipH-2, H-6), 2.90-2.77 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 2.17 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.03 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.81 (2H, qd, J 12.5, 4.0 Hz, 2H of BzpipH-3, H-5), 1.60 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −102.6; m/z: 595 [M+H]⁺.

Compound 475: 6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)-N-(1-(3-methoxybenzyl)piperidin-4-yl)nicotinamide

¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.88 (2H, dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.29-7.20 (3H, m, 2H of C₆H₄F, 1H of C₆ H ₄OCH₃), 6.91-6.88 (2H, m, 2H of C₆H₄OCH₃), 6.79 (1H, m, 1H of C₆H₄OCH₃), 6.35 (1H, d, J 7.5 Hz, NH), 4.83 (1H, m, 1H of BzpipH-2, H-6), 4.12 (1H, m, 1H of BzpipH-2, H-6), 4.03 (1H, m, pipH-4), 3.81 (3H, s, OCH₃), 3.49 (2H, s, CH ₂C₆H₄OCH₃), 3.16 (1H, tt, J 12.0, 3.5 Hz, BzpipH-4), 3.04 (1H, t, J 11.5 Hz, 1H of BzpipH-2, H-6), 2.88-2.74 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 2.16 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.01 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.78 (2H, qd, J 12.5, 4.5 Hz, 2H of BzpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −102.6; m/z: 595 [M+H]⁺.

Compound 476: N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)nicotinamide

¹H nmr (CDCl₃) δ 9.87 (1H, s, NH), 8.89 (1H, m, pyH-6), 8.54 (1H, d, J 2.5 Hz, N, O-pyH-6), 8.44 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.06 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.68 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.35 (1H, d, J 7.5 Hz, pyH-3), 7.25 (2H, m, 2H of C₆H₄F), 7.22 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.03 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.99 (1H, d, J 8.5 Hz, N, O-pyH-3), 3.83 (2H, m, 2H of piz), 3.50 (2H, s, CH ₂C₆H₄F), 3.42, 3.41 (2H, 2d AB system, J 4.5 Hz, 2H of piz), 2.55, 2.53 (2H, 2d AB system, J 4.5 Hz, 2H of piz), 2.40, 2.38 (2H, 2d AB system, J 4.5 Hz, 2H of piz); ¹⁹F nmr (CDCl₃) δ −115.2; m/z: 537 [M+H]⁺.

Compound 491: N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-fluorobenzyl)piperazin-1-yl)pyridazine-3-carboxamide

Compound 491 was prepared as follows:

Step 1

6-Chloropyridazine-3-carboxylic acid (0.96 g, 6.2 mMol) was dissolved in dichloromethane (20 mL) and treated with 4-amino-1-(4-cyanobenzyl)piperidine dihydrochloride (1.79 g, 6.2 mMol), HATU (2.37 g, 6.2 mMol) and DIEA (3.6 mL, 3.3 eq.). The reaction stirred at RT for 3d. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine and then dried over anhydrous sodium sulfate and concentrated under reduced pressure.

The crude product was purified by flash chromatography on silica gel, eluting with 2% methanol in dichloromethane.

¹H NMR (300 MHz, CDCl₃) δ 8.26 (d, J=8.8 Hz, 1H), 7.96 (d, J=10.0 Hz, 1H, NH), 7.68 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 4.02 (m, 1H), 3.15 (m, 2H), 2.81 (m, 2H), 2.29 (m, 2H), 2.12 (m, 2H); m/z=356.05 (M+H)⁺; m/z=354.11 (M−H)⁺

Step 2

The product from step 1 (109 mg, 0.306 mMol) was dissolved in CH₃CN (3 mL) and treated with 4-Fluorobenzylpiperazine (1.2 eq.), tetrabutylammonium iodide (24 mg) and DBU (100 μl). The reaction mixture was then heated at 82° C. for 1.5 h. The reaction mixture was concentrated to dryness and purified by silica gel radial chromatography eluting with 5% methanol in dichloromethane to give Compound 491. ¹H NMR (300 MHz, CDCl₃) δ 7.94 (dd, J=9.6, 1.4 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H, NH), 7.58 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 7.26-7.30 (m, 2H), 6.92-7.02 (m, 3H), 3.97 (m, 1H), 3.73 (m, 4H), 3.52 (s, 2H), 3.49 (s, 2H), 3.12 (m, 2H), 2.77 (m, 2H), 2.54 (m, 4H), 2.20 (m, 2H), 1.97 (m, 2H); m/z=514.18 (M+H)⁺;

For use in the synthesis of Compound 125, 1-(4-fluorobenzyl)-2,2-dimethylpiperazine was synthesized. To a solution of piperazin-2-one (0.500 g, 5.00 mmol, 1.0 eq) in dichloromethane (50 mL) was added trityl chloride (1.533 g, 5.50 mmol, 1.1 eq). The reaction was stirred at room temperature for 18 hours before diluting with CH₂Cl₂ (50 mL). The reaction was washed with NaHCO₃ (100 mL) and brine (100 mL), dried (Na₂SO₄) and concentrated under reduced pressure to yield 4-tritylpiperazin-2-one as a white foam, which was used without further purification; ¹H nmr (CDCl₃) 7.48 (6H, d, J 7.5 Hz, 6H of trityl), 7.28 (6H, m, 6H of trityl), 7.18 (3H, m, 3H of trityl), 5.95 (1H, m, NH), 3.45 (2H, br s, 2H of oxopip), 3.06 (2H, s, 2H of oxopip), 2.46 (2H, br s, 2H of oxopip). A suspension of the 4-tritylpiperazin-2-one (0.405 g, 1.18 mmol, 1.0 eq) in tetrahydrofuran (11 mL) was cooled to 0° C. and 4-fluorobenzyl bromide (0.246 g, 0.16 mL, 1.30 mmol, 1.1 eq) was added followed by sodium hydride (0.057 g of a 60% suspension in oil, 1.42 mmol, 1.2 eq). Dimethylformamide (3 mL) was added to aid dissolution. The reaction mixture was allowed to warm to room temperature with stirring for 14 hours. Additional 4-fluorobenzyl bromide (0.16 mL, 1.1 eq) and sodium hydride (0.057 g, 1.2 eq) was added and the reaction stirred at room temperature for 3 hours and 60° C. for 15 hours. The reaction was cooled and partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with brine (50 mL), water (50 mL) and brine (50 mL), dried (Na₂SO₄) and concentrated under reduced pressure. MPLC (10→30% EtOAc-hexane, 0-15 min then 30→70% EtOAc-hexane 15→25 min) yielded 4-tritylpiperazin-2-one as a white solid (0.374 g, 70%); ¹H nmr (CDCl₃) 7.48 (6H, d, J 7.5 Hz, 3×2H of C₆H), 7.28 (6H, t, J 7.5 Hz, 3×2H of C₆H₅), 7.23-7.15 (5H, m, 3×1H of C₆H₅, 2H of C₆H₄F), 7.01 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 4.78 (2H, s, CH₂C₆H₄F), 3.31 (2H, t, J 5.5 Hz, 2H of oxopip), 3.15 (2H, s, 2H of oxopip), 2.43 (2H, m, 2H of oxopip); m/z 451 [M+H]⁺. A solution of the 4-tritylpiperazin-2-one (0.165 g, 0.367 mmol, 1.0 eq) and di-t-butylpyridine (0.097 mL, 0.440 mmol, 1.2 eq) in dichloromethane (3.5 mL) was cooled to −78° C. Trifluoromethanesulfonic acid (0.074 mL, 0.440 mmol, 1.2 eq) was added and the reaction stirred at −78° C. for 45 minutes before adding methylmagnesium bromide (0.79 mL of a 1.4M solution in toluene, 1.100 mmol, 3.0 eq). The reaction mixture was allowed to stir at −78° C. for 2 hours and warmed to 0° C. over 2 hours before quenching with NH₄Cl (3 mL). The reaction was partitioned between NH₄Cl (50 mL) and CH₂Cl₂ (70 mL). The aqueous phase was extracted with CH₂Cl₂ (2×50 mL) and the combined organics dried (Na₂SO₄) before concentrating under reduced pressure. MPLC (10-30% EtOAc-hexane, 5→18 min) yielded 1-(4-fluorobenzyl)-2,2-dimethyl-4-tritylpiperazine (0.126 g, 74%) as a white solid; m/z 451 [M+H]⁺. To a solution of the 1-(4-fluorobenzyl)-2,2-dimethyl-4-tritylpiperazine (0.126 g, 0.272 mmol, 1.0 eq) in dichloromethane (3.0 mL) was added hydrogen chloride (0.27 mL of a 4M solution in dioxane, 1.086 mmol, 4.0 eq). The reaction was stirred at room temperature for 4 hours. Further hydrogen chloride (0.27 mL of a 4M solution in dioxane, 1.086 mmol, 4.0 eq) was added and the reaction stirred at room temperature for 1 hour before concentrating under reduced pressure. The residue was tritutated with Et₂O (2×10 mL) to yield 1-(4-fluorobenzyl)-2,2-dimethylpiperazine as a white solid, which was was dried under vacuum and used without further purification; ¹H nmr (CD₃OD) 7.62 (2H, m, 2H of C₆H₄F), 7.23 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 3.53 (2H, s, 2H of piz), 3.44 (4H, m, 4H of piz), 1.68 (6H, s, C(CH₃)₂); m/z 223 [M+H]⁺. Syntheses of gem-dimethyl compounds are also generally described in Xiao, K-J.; Luo, J-M.; Ye, K-Y.; Wang, Y.; Huang, P-Q. Angew. Chem. Int. Ed. 2010, 49, 3037-3040.

Synthesis of 1-tert-Butyloxycarbonyl-4-N-methylaminopiperidine

To a solution of 1-tert-butyloxycarbonyl-4-oxopiperidine (0.45 g, 2.26 mmol, 1.0 eq) in dichloromethane (20 mL) was added methylamine (2.26 mL of a 2M solution in tetrahydrofuran, 4.52 mmol, 2.0 eq). After equilibrating at room temperature for 10 minutes, sodium triacetoxyborohydride (0.72 g, 3.39 mmol, 1.5 eq) was added and the reaction stirred at room temperature for 30 minutes. Rochelle's salt (20 mL) was added and the reaction stirred for 1 hour before adding NaHCO₃ (50 mL). The organics were extracted with CH₂Cl₂ (2×100 mL), combined, washed with brine (50 mL), dried (Na₂SO₄) and concentrated under reduced pressure to yield the title compound as a colourless oil; ¹H nmr (CDCl₃) δ 4.03 (2H, m), 2.79 (2H, t, J 12.0 Hz), 2.50 (1H, tt, J 12.0, 3.0 Hz), 2.43 (3H, s), 1.85 (2H, m), 1.47 (9H, s), 1.22 (2H, m); m/z: 215 [M+H]⁺.

Coupling of the 4-N-methylpiperidine

To a mixture of 1-tert-butyloxycarbonyl-4-N-methylaminopiperidine (0.136 g, 0.636 mmol, 1.0 eq) and the pyridine carboxylic acid (0.231 g, 0.636 mmol, 1.0 eq) in dimethylformamide (6 mL) was added triethylamine (0.13 mL, 0.953 mmol, 1.5 eq) followed by HATU (0.214 g, 0.636 mmol, 1.0 eq). The reaction was stirred at room temperature for 4 hours before partitioning between EtOAc (100 mL) and NaHCO3-water (1:1, 100 mL). The organics were further washed with brine (100 mL), water (100 mL) and brine (100 mL) before drying (Na₂SO₄) and concentrating under reduced pressure. MPLC (0 10% MeOH—CH₂Cl₂) yielded the coupled material (0.215 g, 61%) as a white foam; ¹H nmr (CDCl₃) δ 8.60 (1H, s, pyH-6), 7.92 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.80 (1H, d, J 9.0 Hz, pyH-3 or pyH-6), 7.67 (1H, d, J 9.0 Hz, pyH-3 or pyH-4), 6.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.63 (1H, m, 1H of BzpipH-2, H-6), 4.23 (1H, m, pipH-4), 3.98 (1H, m, 1H of BzpipH-2, H-6), 3.86 (3H, s, OCH₃), 3.52 (1H, m, BzpipH-4), 3.25 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.97 (1H, m, 1H of pipH-2, H-3, H-5, H-6), 2.82 (3H, br s. NCH₃), 2.55 (1H, m, 1H of pipH-2, H-3, H-5, H-6), 1.97 (1H, m, 1H of pipH-2, H-3, H-5, H-6, BzpipH-3, H-5), 1.92-1.66 (9H, m, 9H of pipH-2, H-3, H-5, H-6, BzpipH-3, H-5), 1.45 (9H, s, C(CH₃)₃); m/z: 565 [M+H]⁺.

Synthesis of 1-tert-Butyloxycarbonyl-3,3-difluoro-4-aminopiperidine 1-tert-Butyloxycarbonyl-3,3-difluoro-4-benzylaminopiperidine

To a solution of 1-tert-butyloxycarbonyl-3,3-difluoro-4-oxopiperidine (Synthonix, 0.100 g, 0.426 mmol, 1.0 eq) in dichloromethane (1.5 mL) was added benzylamine (0.070 mL, 0.638 mmol, 1.5 eq) followed by sodium triacetoxyborohydride (0.180 g, 0.851 mmol, 2.0 eq). The reaction was stirred at room temperature for 16 hours before adding Rochelle's salt (2 mL) and stirring for 1 hour. The reaction mixture was partitioned between NaHCO₃ (50 mL) and CH₂Cl₂ (50 mL). The aqueous phase was extracted with CH₂Cl₂ (2×50 mL). The combined organics were washed with brine (50 mL), dried (Na₂SO₄) and concentrated under reduced pressure. MPLC (30→70% EtOAc-hexane) yielded the title compound (0.045 g, 32%) as a colourless oil; ¹H nmr (CDCl₃) δ 7.33 (4H, m, 4H of C₆H₅), 7.27 (1H, m, 1H of C₆H₅), 4.02 (1H, m), 3.92 (2H, s, CH ₂C₆H₅), 3.76 (1H, m), 3.32 (1H, ddd, J 21.5, 14.0, 4.5 Hz), 3.11 (1H, m), 2.97 (1H, m), 1.90 (1H, m), 1.67-1.59 (1H, m), 1.46 (9H, s, C(CH₃)₃); ¹⁹F nmr (CDCl₃) δ −109.0 (dd, J 243.0, 115.5 Hz), −119.5 (d, J 251.0 Hz); m/z: 327 [M+H]⁺.

1-tert-Butyloxy-3,3-difluoro-4-aminopiperidine

Palladium hydroxide (approx. 0.030 g) was added to a solution of the benzylaminopiperidine (0.045 g, 0.138 mmol) in ethanol (3.0 mL). The flask was purged with hydrogen and the reaction stirred under an atmosphere of hydrogen for 2 hours. The flask was purged with nitrogen and the reaction filtered through celite, eluting with 5% MeOH—CH₂Cl₂ (4×5 mL). The filtrate was concentrated under reduced pressure to yield the title compound as a colourless oil, which was used without purification;

Coupling of the 3,3-difluoro-4-aminopiperidine to the pyridine carboxylic acid

To a solution of the difluoroaminopiperidine (0.035 g, 0.148 mmol, 1.0 eq) and the pyridine carboxylic acid (0.055 g, 0.148 mmol, 1.0 eq) in dimethylformamide (1.5 mL) was added triethylamine (0.031 mL, 0.222 mmol, 1.5 eq) followed by HATU (0.056 g, 0.148 mmol, 1.0 eq). The resulting yellow solution was stirred at room temperature for 5 hours before partitioning between EtOAc (100 mL) and NaHCO₃-water (1:1, 100 mL). The organics were further washed with brine (100 mL), water (100 mL) and brine (100 mL) before drying (Na₂SO₄) and concentrating under reduced pressure. MPLC (0→10% MeOH—CH₂Cl₂) yielded the diamide (0.057 g, 67%) as a white foam; ¹H nmr (CDCl₃) δ 8.97 (1H, s, pyH-6), 8.17 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.5 Hz, 2H of C₆ H ₄OCH₃), 7.60 (1H, d, J 8.5 Hz, pyH-4), 7.07 (1H, m, NH), 6.94 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 4.66 (1H, m, 1H of BzpipH-2, H-6), 4.55 (1H, m, 1H of pipH-2), 4.42 (1H, m, 1H of pipH-2), 4.19 (1H, m, pipH-4), 3.90 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, OCH3), 3.52 (1H, m, BzpipH-4), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 3.05-2.87 (2H, m, pipH-6), 2.04-1.99 (2H, m, 2H of pipH-5. BzpipH-3, H-5), 1.91-1.67 (4H, m, 4H of pipH-5, BzpipH-3, H-5), 1.46 (9H, s, C(CH₃)₃); m/z: 587 [M+H]⁺.

Syntheses of (cis)- and (trans)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate

For use in the synthesis of various compounds described above, (cis)- and (trans)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate were prepared as described in the scheme below:

Example 2 Increase in AMPK Activity

Compounds were assayed for their ability to activate AMPK using an enzyme-linked immunosorbent assay. Reagents and procedures for measuring AMPK activation are well known and kits for AMPK activation assays are commercially available. The EC₅₀ values for AMPK activation for compounds 1-498 are presented in Table 2 below, in which “A” is less than 0.5 μM; “B” is 0.5-1 μM; “C” is 1-5 μM; and “D” is 5-10 μM; and “E” is >10 μM:

TABLE 2 Cpd No. AMPK EC₅₀ 1 A 2 E 3 B 4 B 5 B 6 B 7 A 8 A 9 A 10 A 11 A 12 D 13 C 14 B 15 C 16 A 17 E 18 A 19 F 20 F 21 A 22 A 23 A 24 A 25 A 26 A 27 B 28 B 29 B 30 C 31 A 32 B 33 D 34 C 35 B 36 B 37 D 38 B 39 C 40 C 41 E 42 C 43 C 47 A 48 B 49 A 50 A 51 A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 A 64 A 65 A 66 A 67 A 68 A 69 A 70 A 72 A 73 D 74 A 75 C 76 A 77 A 78 A 79 B 80 C 81 B 82 B 83 E 84 C 85 C 86 C 87 C 88 C 89 C 90 E 91 E 92 E 93 E 94 E 95 A 96 E 97 C 98 C 99 D 100 A 101 A 102 D 103 A 104 A 105 E 106 D 107 D 108 B 109 D 110 C 111 C 112 C 113 C 114 C 115 D 116 C 117 A 118 A 119 C 120 E 121 C 122 A 123 A 124 A 125 A 126 A 127 A 128 A 129 A 130 A 131 A 132 A 133 A 134 A 135 A 136 A 137 A 138 A 139 A 140 A 141 B 142 A 143 A 144 B 145 A 146 A 147 A 149 B 150 A 151 A 152 A 153 C 154 A 155 A 156 A 157 A 158 A 159 C 160 A 161 A 162 A 163 A 164 B 165 A 166 A 167 A 168 A 169 B 170 E 171 A 172 A 173 A 174 A 175 A 176 C 177 C 178 A 179 A 180 A 181 A 182 A 183 A 184 A 185 A 186 A 187 C 188 B 189 C 190 A 191 A 192 A 193 A 194 A 195 A 196 A 197 A 198 A 199 A 200 A 201 B 202 A 203 A 204 A 205 A 206 A 207 A 208 A 209 A 210 E 211 A 212 A 213 A 214 E 215 E 216 E 217 E 218 A 219 A 220 A 221 C 222 C 223 C 224 A 225 A 226 A 227 A 228 A 229 C 230 B 231 A 232 A 233 A 234 A 235 A 236 A 237 C 238 C 239 C 240 A 241 A 242 A 243 A 244 D 245 A 246 A 247 A 248 A 249 A 250 A 251 A 252 B 253 B 254 A 255 A 256 A 257 A 258 A 259 A 260 A 261 A 262 A 263 A 264 D 265 C 266 A 267 A 268 A 269 A 270 A 271 A 272 A 273 A 274 E 275 A 276 A 277 A 278 A 279 A 280 A 281 A 282 A 283 A 284 A 285 A 286 A 287 A 288 A 289 A 290 A 291 A 292 A 293 A 294 A 295 A 296 A 297 A 298 A 299 A 300 A 301 A 302 A 303 A 304 A 305 A 306 A 307 B 308 A 309 A 310 A 311 A 312 A 313 A 314 E 315 A 316 A 317 A 318 A 319 A 320 A 321 A 322 A 323 A 324 A 325 A 326 A 327 A 328 A 329 A 330 B 331 A 332 A 333 A 334 A 335 E 336 A 337 A 338 A 339 A 340 A 341 A 342 A 343 A 344 A 345 A 346 A 347 A 348 A 349 A 350 A 351 A 352 A 353 A 354 A 355 E 356 A 357 A 358 A 359 A 360 A 361 A 362 A 363 A 364 A 365 A 366 A 367 E 368 A 369 A 370 A 371 E 372 A 373 A 374 E 375 A 376 A 377 A 378 A 379 A 380 A 381 A 382 A 383 E 384 B 385 E 386 E 387 A 388 A 389 C 390 A 391 A 392 A 393 A 394 E 395 A 396 C 397 A 398 A 399 A 400 C 401 C 402 A 403 E 404 C 405 A 406 B 407 A 408 A 409 A 410 A 411 C 412 C 413 C 414 C 415 A 416 C 417 A 418 A 419 A 420 C 421 C 422 C 423 A 424 A 425 A 426 A 427 C 428 B 429 B 430 A 431 B 432 B 433 A 434 A 435 A 436 A 437 A 438 A 439 A 440 A 441 A 442 A 443 A 444 A 445 E 446 A 447 A 448 C 449 C 450 A 451 A 452 A 453 A 454 A 455 A 456 A 457 A 458 A 459 A 460 A 461 A 462 A 463 A 464 A 465 A 466 A 467 C 468 A 469 A 470 A 471 C 472 C 473 C 474 C 475 C 476 A 477 A 478 A 479 A 480 A 481 A 482 A 483 A 484 A 485 A 486 A 487 C 488 A 489 A 490 C 491 C 492 A 493 A 494 A 495 A 496 A 497 A 498 A 

What is claimed is:
 1. A method for treating a disease or disorder selected from the group consisting of type II diabetes, atherosclerosis, obesity, non-alcoholic fatty liver disease, diseases and disorders linked to elevated ceramide levels in a subject, diseases and disorders in which cell proliferation is deficient or desired in a subject, disorders of aging, disorders of mitochondrial function, muscular dystrophic states, neurological disorders associated with reduced mitochondrial function, oxidative stress or both, hypoxic states, angina pectoris, coronary ischemia and organ damage secondary to coronary vessel occlusion, intermittent claudication, multi-infarct dementia, myocardial infarction, stroke, high altitude sickness and heart failure, including congestive heart failure ischemia, ischemic reperfusion injury, myocardial ischemia or infarction, cerebrovascular accidents, operative ischemia, traumatic hemorrhage, resuscitation injury, spinal cord trauma, inflammatory diseases, Down's syndrome, Hallervorden-Spatz disease, Huntingtons chorea, Wilson's disease, diabetic angiopathy, uveitis, chronic obstructive pulmonary disease (COPD), asthma, neoplasia, Crohn's disease, inflammatory bowel disease, pancreatitis and age-related disorders, or for activating the AMPK pathway, up-regulating ceramidase activity, reducing triglyceride levels, increasing insulin sensitivity, increasing metabolic efficiency, increasing fiber oxidative capacity, increasing endurance, increasing aerobic workload, reducing oxidative stress, reducing free radical damage, reducing organ inflammation, mimicking the effects of exercise, retarding cellular responses associated with the activation of the ceramide-mediated signal transduction pathway, reducing the effect of aging on the skin, treating radiation and dermatitis in the skin in a subject, the method comprising administering to the subject an effective amount of a compound having the structural formula

or a pharmaceutically acceptable salt- or N-oxide thereof, wherein R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄ alkyl); G is —CH₂—, —C(O)—, —S(O)₂—, —CH(CH₃)—, —C(CH₃)₂—, —O—, —C(O)—NH—, —C(O)—NH—CH₂—, —CH₂CH₂—, a single bond, —OCH₂—, CH₂CH₂O—, —CH(COOMe)- or —CH(COOEt)-; R¹⁷ is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃, —SF₅, —NO₂ and —CN; each R³ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN; w is 0, 1, 2 or 3; each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R⁴ on the same carbon optionally combine to form oxo, and two R⁴ on different carbons optionally combine to form a —(C₀-C₄ alkylene)- bridge; x is 0, 1, 2, 3 or 4; J is absent, —C(O)—, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—, in which R¹³ is selected from —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl); the ring system denoted by “B” is absent, arylene, heteroarylene

wherein each of Y¹ and Y² is N, C or CH, provided that at least one of Y¹ and Y² is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6, or

wherein Y¹ is N or C and Y² is N, C or CH, provided that at least one of Y¹ and Y² is N, the ring system denoted by “C” is an arylene or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6; Q is a single bond, —CH₂—, —CH₂O—, —OCH₂CH₂—, —CH₂CH₂—, —O—, —CHF—, —CH(CH₃)—, —C(CH₃)₂—, —CH(OH)—, —CH(COOMe)-, —CH(COOEt)-, —C(O)— or —S(O)₂—; the ring system denoted by “A” is heteroaryl or aryl; each R⁵ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃, —SF₅, —NO₂ and —CN; and y is 0, 1, 2, 3 or 4; in which each L is independently selected from —NR⁹C(O)O—, —OC(O)NR⁹—, —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—, —SC(O)NR⁹—, —NR⁹C(O)—, —C(O)—NR⁹—, —NR⁹C(S)O—, —OC(S)NR⁹—, —NR⁹C(S)—NR⁹—, —NR⁹C(S)S—, —SC(S)NR⁹—, —NR⁹C(S)—, —C(S)NR⁹—, —SC(O)NR⁹—, —NR⁹C(S)—, —S(O)₀₋₂—, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR⁹C(NR²)NR⁹—, —NR⁹SO₂—, —SO₂NR⁹— and —NR⁹SO₂NR⁹—, each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and each R⁹ is independently selected from —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl).
 2. The method according to claim 1, wherein x is
 0. 3. The method according to claim 1, wherein the ring system denoted by “B” is arylene or heteroarylene.
 4. The method according to claim 1, wherein the ring system denoted by “B” is


5. A method according to claim 4, wherein R¹⁷ is aryl optionally substituted with 1, 2 or 3 substituents independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃, —SF₅, —NO₂ and —CN.
 6. The method according to claim 1, wherein J is —NR¹³— or —NR¹³C(O)—.
 7. The method according to claim 1, wherein J is —C(O)NR¹³— or —C(O)—.
 8. The method according to claim 1, wherein the compound has the structural formula


9. The method according to claim 1, wherein the compound has the structural formula

in which J is absent, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—.
 10. The method according to claim 1, wherein the

moiety is


11. The method according to claim 1, wherein the

moiety is


12. The method according to claim 1, wherein the

moiety is


13. The method according to claim 1, wherein the

moiety is


14. A method according to claim 1, wherein the

moiety is


15. The method according to claim 14, wherein each R³ is independently selected from the group consisting of —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN; each R⁴ is independently selected from the group consisting of —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R4 optionally combine to form oxo; each R⁵ is independently selected from the group consisting of —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃, —SF₅, —NO₂ and —CN, R¹⁷ is aryl or heteroaryl, optionally substituted 1, 2 or 3 substituents independently selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen —NO₂ and —CN, wherein each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl).
 16. The method according claim 15, wherein R¹⁷ is phenyl substituted with 0, 1 or 2 R³⁰, and the

moiety is phenyl substituted with 0, 1 or 2 R³⁰, wherein each R³⁰ is independently selected from halogen, unsubstituted (C₁-C₆ alkoxy), —(C₁-C₆ haloalkoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³ and —(NH)₀₋₁COR³³, in which each R³³ is (unsubstituted C₁-C₆ alkyl) or (C₁-C₆ haloalkyl).
 17. The method according to claim 1, wherein J is —C(O)—.
 18. The method according to claim 17, wherein the

moiety has the structural formula


19. The method according to claim 17, wherein the

moiety has the structural formula


20. The method according to claim 1, wherein the compound has structural formula


21. The method according to claim 1, wherein the compound has structural formula


22. The method according to claim 1, wherein each R³ is independently selected from the group consisting of —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN; each R⁴ is independently selected from the group consisting of —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R4 optionally combine to form oxo; each R⁵ is independently selected from the group consisting of —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃, —SF₅, —NO₂ and —CN, R¹⁷ is aryl or heteroaryl, optionally substituted 1, 2 or 3 substituents independently selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, wherein each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl).
 23. The method according to claim 1, wherein w is
 0. 24. The method according to claim 1, wherein x is 0 and w is
 0. 25. The method according to claim 1, wherein G is —CH₂—, —C(O)—, or —S(O)₂—; R¹⁷ is phenyl or monocyclic heteroaryl substituted with 0, 1 or 2 R³⁰; each R³ is independently selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy, —SO₂Me, -halogen, —NO₂ and —CN; w is 0 or 1; J is absent, —C(O)—, —NH—, —NHC(O)— or —C(O)NH—; the ring system denoted by “B” is

wherein each of Y¹ and Y² is N, C or CH, provided that at least one of Y¹ and Y² is N; T is

 wherein Q is a single bond, —CH₂—, —O—, —C(O)— or —S(O)₂—; the ring system denoted by “A” is phenyl or monocyclic heteroaryl; and y is 0, 1, 2 or 3; in which each R³⁰ is independently selected from halogen, unsubstituted (C₁-C₆ alkoxy), —(C₁-C₆ haloalkoxy), —SH, —S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³ and —(NH)₀₋₁COR³³, in which each R³³ is (unsubstituted C₁-C₆ alkyl) or (C₁-C₆ haloalkyl).
 26. The method according to claim 25, wherein w is
 0. 27. The method according to claim 1, wherein the method is for treating type II diabetes, treating atherosclerosis, treating obesity, treating non-alcoholic fatty liver disease, reducing triglyceride levels or increasing insulin sensitivity in the subject.
 28. The method according to claim 1, wherein the method is for activating the AMPK pathway in the subject.
 29. The method according to claim 1, wherein the method is for treating a disease or disorder in which cell proliferation is deficient or desired in a subject.
 30. The method according to claim 1, wherein the method is for treating intermittent claudication in a subject. 